U.S. patent application number 14/963065 was filed with the patent office on 2016-03-31 for sensors for continuous analyte monitoring, and related methods.
The applicant listed for this patent is DexCom, Inc.. Invention is credited to Jennifer Blackwell, Sebastian Bohm, Peter C. Simpson.
Application Number | 20160089065 14/963065 |
Document ID | / |
Family ID | 50475958 |
Filed Date | 2016-03-31 |
United States Patent
Application |
20160089065 |
Kind Code |
A1 |
Simpson; Peter C. ; et
al. |
March 31, 2016 |
SENSORS FOR CONTINUOUS ANALYTE MONITORING, AND RELATED METHODS
Abstract
Sensor devices including dissolvable tissue-piercing tips are
provided. The sensor devices can be used in conjunction with
dissolvable needles configured for inserting the sensor devices
into a host. Hardening agents for strengthening membranes on sensor
devices are also provided. Methods of using and fabricating sensor
devices are also provided.
Inventors: |
Simpson; Peter C.; (Cardiff,
CA) ; Blackwell; Jennifer; (San Diego, CA) ;
Bohm; Sebastian; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DexCom, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
50475958 |
Appl. No.: |
14/963065 |
Filed: |
December 8, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13780808 |
Feb 28, 2013 |
|
|
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14963065 |
|
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|
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61713338 |
Oct 12, 2012 |
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Current U.S.
Class: |
600/347 |
Current CPC
Class: |
A61B 5/6848 20130101;
A61B 2017/00004 20130101; A61B 17/3468 20130101; A61B 5/14532
20130101; A61B 5/14865 20130101; A61B 5/4839 20130101; A61B 5/1473
20130101; A61B 5/14503 20130101 |
International
Class: |
A61B 5/1473 20060101
A61B005/1473; A61B 5/00 20060101 A61B005/00; A61B 17/34 20060101
A61B017/34; A61B 5/145 20060101 A61B005/145 |
Claims
1-20. (canceled)
21. A sensor device for measuring an analyte concentration in a
host, comprising: an in vivo portion configured for insertion under
a host's skin, wherein the in vivo portion comprises: a sensor
comprising at least one electrode and a membrane covering at least
a portion of the at least one electrode, wherein the sensor
comprises a blunt distal end; and a biodegradable material
surrounding the distal end of the sensor, wherein the biodegradable
material degrades following insertion into the host; and an ex vivo
portion configured to remain above the host's skin surface after
insertion of the in vivo portion, wherein the ex vivo portion is
configured to receive direct pressure from a user for insertion of
the in vivo portion of the sensor device, wherein the ex vivo
portion comprises an adhesive configured to adhere the ex vivo
portion to the host's skin.
22. The sensor device of claim 21, wherein the biodegradable
material dissolves within three hours after insertion into the
host.
23. The sensor device of claim 21, wherein the biodegradable
material provide sufficient column strength to the sensor such that
the sensor can be inserted through the host's skin without
substantial buckling.
24. The sensor device of claim 21, wherein the in vivo portion has
a length of from about 1 mm to about 7 mm.
25. The sensor device of claim 21, wherein the at least one
electrode comprises a working electrode and a reference
electrode.
26. The sensor device of claim 21, wherein the ex vivo portion
comprises a sensor electronics unit operatively and detachably
connected to the sensor.
27. The sensor device of claim 26, wherein the sensor electronics
unit is configured to be located over a sensor insertion site.
28. The sensor device of claim 26, wherein the electrode is
electrically connected to sensor electronics prior to insertion of
the in vivo portion.
29. The sensor device of claim 21, wherein the in vivo portion is
configured to be inserted without a removable needle.
30. The sensor device of claim 21, wherein the ex vivo portion
comprises a guiding portion configured to provide guidance and
support to the in vivo portion as the in vivo portion is inserted
through the skin of the host.
31. The sensor device of claim 21, wherein the biodegradable
material surrounding the distal end is configured to be dissolved
from 1 hour to 1 day after insertion into the host.
32. The sensor device of claim 31, wherein the biodegradable
material surrounding the distal end is configured to be dissolved
from 1 hour to 12 hours after insertion into the host.
33. The sensor device of claim 21, wherein the biodegradable
material is a material that pulls fluid to tissue surrounding the
in vivo portion.
Description
INCORPORATION BY REFERENCE TO RELATED APPLICATIONS
[0001] Any and all priority claims identified in the Application
Data Sheet, or any correction thereto, are hereby incorporated by
reference under 37 CFR 1.57. This application is a continuation of
U.S. application Ser. No. 13/780,808 filed Feb. 28, 2013, which
claims the benefit of U.S. Provisional Application No. 61/713,338
filed Oct. 12, 2012. Each of the aforementioned applications is
incorporated by reference herein in its entirety, and each is
hereby expressly made a part of this specification.
TECHNICAL FIELD
[0002] The present embodiments relate to systems and methods for
measuring an analyte concentration in a host.
BACKGROUND
[0003] Diabetes mellitus is a disorder in which the pancreas cannot
create sufficient insulin (Type I or insulin dependent) and/or in
which insulin is not effective (Type 2 or non-insulin dependent).
In the diabetic state, the victim suffers from high blood sugar,
which may cause an array of physiological derangements associated
with the deterioration of small blood vessels, for example, kidney
failure, skin ulcers, or bleeding into the vitreous of the eye. A
hypoglycemic reaction (low blood sugar) may be induced by an
inadvertent overdose of insulin, or after a normal dose of insulin
or glucose-lowering agent accompanied by extraordinary exercise or
insufficient food intake.
[0004] Conventionally, a person with diabetes carries a
self-monitoring blood glucose (SMBG) monitor, which typically
requires uncomfortable finger pricks to obtain blood samples for
measurement. Due to the lack of comfort and convenience associated
with finger pricks, a person with diabetes normally only measures
his or her glucose levels two to four times per day. Unfortunately,
time intervals between measurements may be spread far enough apart
that the person with diabetes finds out too late of a hyperglycemic
or hypoglycemic condition, sometimes incurring dangerous side
effects. It is not only unlikely that a person with diabetes will
take a timely SMBG value, it is also likely that he or she will not
know if his or her blood glucose value is going up (higher) or down
(lower) based on conventional methods. Diabetics thus may be
inhibited from making educated insulin therapy decisions.
[0005] Another device that some diabetics use to monitor their
blood glucose is a continuous analyte sensor. A continuous analyte
sensor typically includes a sensor that is placed subcutaneously,
transdermally (e.g., transcutaneously), or intravascularly. The
sensor measures the concentration of a given analyte within the
body, and generates a raw signal that is transmitted to electronics
associated with the sensor. The raw signal is converted into an
output value that is displayed on a display. The output value that
results from the conversion of the raw signal is typically
expressed in a form that provides the user with meaningful
information, such as blood glucose expressed in mg/dL.
SUMMARY
[0006] The various present embodiments have several features, no
single one of which is solely responsible for their desirable
attributes. Without limiting the scope of the present embodiments
as expressed by the claims that follow, their more prominent
features now will be discussed briefly. After considering this
discussion, and particularly after reading the section entitled
"Detailed Description," one will understand how the features of the
present embodiments provide the advantages described herein.
[0007] One aspect of the present embodiments includes the
realization that tack sensors include a sharpened tip that remains
implanted in the tissue throughout the usable life of the sensor.
Leaving the sharpened tip in vivo for an extended period of time
may cause trauma to surrounding tissue, leading to scarring and
inhibition of wound healing. Some of the present embodiments
provide solutions to this problem.
[0008] In recognition of the foregoing problem, in a first aspect
certain of the present embodiments comprise a sensor device for
measuring an analyte concentration in a host, the sensor device
comprising: a sensor unit comprising a sensor body, at least one
electrode, and a membrane covering at least a portion of the at
least one electrode, the sensor body having a blunt tip; a piercing
element comprising a material that rapidly dissolves upon insertion
into the host, the piercing element abutting the sensor tip and
being capable of piercing tissue; and a mounting unit spaced from
the sensor tip and configured to support the sensor device on an
exterior surface of the host's skin.
[0009] In an embodiment of the first aspect, the piercing element
is secured to the sensor tip.
[0010] In an embodiment of the first aspect, the piercing element
is adhered to the sensor tip.
[0011] In an embodiment of the first aspect, the piercing element
is not secured to the sensor tip, but is maintained in abutting
contact therewith.
[0012] In an embodiment of the first aspect, a sleeve surrounding
the sensor tip and the piercing element maintains the abutting
contact.
[0013] In an embodiment of the first aspect, the piercing element
comprises a coating that covers at least a portion of the sensor
body including the sensor tip.
[0014] In an embodiment of the first aspect, the coating comprises
a sharp coating tip.
[0015] In an embodiment of the first aspect, the material of the
piercing element comprises a material that suppresses wounding.
[0016] In an embodiment of the first aspect, the material of the
piercing element comprises a material that promotes rapid wound
healing.
[0017] In an embodiment of the first aspect, the material of the
piercing element comprises a material that induces osmotic pressure
or oncotic pressure.
[0018] In an embodiment of the first aspect, the material of the
piercing element comprises one or more drugs.
[0019] In an embodiment of the first aspect, the material of the
piercing element comprises a vascular endothelial growth factor
(VEGF).
[0020] In an embodiment of the first aspect, the material of the
piercing element comprises at least one of a salt, a metallic salt,
a sugar, a synthetic polymer, polylactic acid, polyglycolic acid,
or a polyphosphazene.
[0021] In an embodiment of the first aspect, the material of the
piercing element biodegrades/dissolves within a first day after
insertion into the host.
[0022] In an embodiment of the first aspect, the material of the
piercing element biodegrades/dissolves within three hours after
insertion into the host.
[0023] In an embodiment of the first aspect, the piercing element
does not extend past the sensor tip in the direction of the
mounting unit, or extends only a nominal amount in said
direction.
[0024] In an embodiment of the first aspect, the piercing element
extends past the sensor tip in the direction of the mounting unit,
but stops short of the electrode.
[0025] In an embodiment of the first aspect, the mounting unit
comprises a guiding portion configured to guide insertion of the
sensor unit through the host's skin and to support a column
strength of the sensor body such that the sensor unit is capable of
being inserted through the host's skin without substantial
buckling.
[0026] In an embodiment of the first aspect, the at least one
electrode comprises a working electrode and a reference
electrode.
[0027] In an embodiment of the first aspect, the sensor body
further comprises a support member configured to protect the
membrane from damage during insertion of the sensor unit.
[0028] In an embodiment of the first aspect, the at least one
electrode is the support member.
[0029] In an embodiment of the first aspect, the support member is
configured to support at least a portion of the at least one
electrode.
[0030] In an embodiment of the first aspect, the support member is
configured to substantially surround the at least one
electrode.
[0031] In an embodiment of the first aspect, the mounting unit
comprises a sensor electronics unit operatively and detachably
connected to the sensor body.
[0032] In an embodiment of the first aspect, the sensor electronics
unit is configured to be located over a sensor insertion site.
[0033] Also in recognition of the foregoing problem, in a second
aspect certain of the present embodiments comprise a method of
making a sensor device, the method comprising: dipping a tip of a
sensor into a liquid to form a coating of the liquid on the sensor
tip; and withdrawing the sensor tip from the liquid while
controlling parameters of the withdrawal so that the coating forms
a sharp point extending from the sensor tip, the sharp point being
capable of piercing tissue.
[0034] In an embodiment of the second aspect, the parameters
include at least one of a length (L) of the sensor that is wetted
by the liquid, a viscosity of the liquid, and a withdrawal
rate.
[0035] In an embodiment of the second aspect, L is in the range of
0.1-4 mm.
[0036] In an embodiment of the second aspect, L is 2-3 mm.
[0037] In an embodiment of the second aspect, the viscosity is
below 100 cP.
[0038] In an embodiment of the second aspect, the withdrawal rate
is 20-30 in/sec.
[0039] In an embodiment of the second aspect, the method further
comprises curing the coating.
[0040] In an embodiment of the second aspect, the curing comprises
UV (or heat) cross-linking, irradiating, drying, or heating.
[0041] In an embodiment of the second aspect, the method further
comprises using a tip mold or draw-through fixture that clamps and
cures in one step in order to form a sharp cone shape.
[0042] In an embodiment of the second aspect, the method further
comprises applying a voltage to the coating while it is being
cured.
[0043] In an embodiment of the second aspect, the method further
comprises heating the coating and drawing it out like glass.
[0044] Another aspect of the present embodiments includes the
realization that in some current methods for sensor insertion the
sensor is received within the lumen of an insertion needle. The
needle, which has greater column strength than the sensor, bears
the frictional forces that occur during insertion. Once the sensor
is in place in the tissue, the needle is removed. The need to
remove the needle adds complexity to the insertion process,
including the need to electrically connect the sensor to sensor
electronics after insertion. Some of the present embodiments
provide solutions to this problem.
[0045] In recognition of the foregoing problem, in a third aspect
certain of the present embodiments comprise a sensor device for
measuring an analyte concentration in a host, the sensor device
comprising: a sensor unit comprising a sensor body, at least one
electrode, and a membrane covering at least a portion of the at
least one electrode; and a piercing element comprising a material
that rapidly dissolves upon insertion into the host, the piercing
element including a sharp tip capable of piercing tissue, and a
lumen that receives the sensor unit.
[0046] In an embodiment of the third aspect, the sensor body has a
blunt tip.
[0047] In an embodiment of the third aspect, the sensor unit is not
secured to the piercing element.
[0048] In an embodiment of the third aspect, the sensor unit is
secured to the piercing element.
[0049] In an embodiment of the third aspect, the material of the
piercing element comprises a material that suppresses wounding.
[0050] In an embodiment of the third aspect, the material of the
piercing element comprises a material that promotes rapid wound
healing.
[0051] In an embodiment of the third aspect, the material of the
piercing element comprises a material that induces osmotic pressure
or oncotic pressure.
[0052] In an embodiment of the third aspect, the material of the
piercing element comprises one or more drugs.
[0053] In an embodiment of the third aspect, the material of the
piercing element comprises a vascular endothelial growth factor
(VEGF).
[0054] In an embodiment of the third aspect, the material of the
piercing element comprises at least one of a salt, a metallic salt,
a sugar, a synthetic polymer, polylactic acid, polyglycolic acid,
or a polyphosphazene.
[0055] In an embodiment of the third aspect, the material of the
piercing element biodegrades/dissolves within a first day after
insertion into the host.
[0056] In an embodiment of the third aspect, the material of the
piercing element biodegrades/dissolves within three hours after
insertion into the host.
[0057] Another aspect of the present embodiments includes the
realization that the material of analyte sensor membranes is soft,
and tends to peel back as the sensor advances into tissue. This
problem is especially acute for sensors that are formed by a
process in which they are first coated with a membrane and then
sharpened at the tip. This process exposes the sensor body, and
leaves a thin coating of the membrane surrounding the sides of the
sensor body at the tip. Some of the present embodiments provide
solutions to this problem.
[0058] In recognition of the foregoing problem, in a fourth aspect
certain of the present embodiments comprise a sensor device for
measuring an analyte concentration in a host, the sensor device
comprising: a sensor unit comprising a sensor body, at least one
electrode, and a membrane covering at least a portion of the at
least one electrode; and a mounting unit spaced from the sensor tip
and configured to support the sensor device on an exterior surface
of the host's skin; wherein the membrane comprises a hardening
agent, the hardening agent providing increased column strength to
the sensor unit so that the sensor unit is capable of being
inserted through the host's skin without substantial buckling.
[0059] In an embodiment of the fourth aspect, the hardening agent
is integrated with the membrane. body.
[0060] In an embodiment of the fourth aspect, a tip of the sensor
body is exposed through the membrane.
[0061] In an embodiment of the fourth aspect, the exposed tip of
the sensor body comprises a material that does not react with
hydrogen peroxide.
[0062] In an embodiment of the fourth aspect, the hardening agent
comprises cyanoacrylate.
[0063] Also in recognition of the foregoing problem, in a fifth
aspect certain of the present embodiments comprise a sensor device
for measuring an analyte concentration in a host, the sensor device
comprising: a sensor unit comprising a sensor body, at least one
electrode, and a membrane covering at least a portion of the at
least one electrode; and a mounting unit spaced from the sensor tip
and configured to support the sensor device on an exterior surface
of the host's skin; wherein the membrane comprises a hardening
agent, the hardening agent increasing a column strength of the
sensor unit and increasing an adhesion of the membrane to the at
least one electrode; and wherein the membrane comprising the
hardening agent allows analyte permeability.
[0064] In an embodiment of the fifth aspect, the hardening agent is
suspended in a matrix.
[0065] In an embodiment of the fifth aspect, the membrane covers a
tip of the sensor.
[0066] In an embodiment of the fifth aspect, a tip of the sensor is
exposed through the membrane.
[0067] In an embodiment of the fifth aspect, the exposed tip of the
sensor comprises a material that does not react with hydrogen
peroxide.
[0068] In an embodiment of the fifth aspect, the hardening agent
comprises cyanoacrylate.
[0069] Also in recognition of the foregoing problem, in a sixth
aspect certain of the present embodiments comprise a method of
making a sensor device, the method comprising: coating a wire with
a membrane; cutting the coated wire to a desired length to thereby
form a sensor tip; and exposing the coated wire to a hardening
agent such that the membrane absorbs the hardening agent.
[0070] In an embodiment of the sixth aspect, exposing the coated
wire comprises dipping at least the sensor tip in the hardening
agent.
[0071] In an embodiment of the sixth aspect, certain of the present
embodiments further comprise curing the membrane to harden the
hardening agent.
[0072] In an embodiment of the sixth aspect, certain of the present
embodiments further comprise sharpening the sensor tip to form a
sharp point capable of piercing tissue.
[0073] In an embodiment of the sixth aspect, the sensor tip
comprises a material that does not react with hydrogen
peroxide.
[0074] In an embodiment of the sixth aspect, certain of the present
embodiments further comprise applying a deadening agent to the
sharpened sensor tip to deaden any active surfaces exposed during
the sharpening step.
[0075] In an embodiment of the sixth aspect, the deadening agent
comprises cyanoacrylate or silane.
[0076] In an embodiment of the sixth aspect, the deadening agent is
applied using vapor deposition.
[0077] In an embodiment of the sixth aspect, the hardening agent
comprises cyanoacrylate.
[0078] Also in recognition of the foregoing problem, in a seventh
aspect certain of the present embodiments comprise a method of
making a sensor device, the method comprising: cutting a wire to a
desired length to thereby form a sensor tip; sharpening the sensor
tip to form a sharp point capable of piercing tissue; coating the
wire, including the sharpened sensor tip, with a membrane; and
exposing the coated wire to a hardening agent such that the
membrane absorbs the hardening agent.
[0079] In an embodiment of the seventh aspect, exposing the coated
wire comprises dipping at least the sensor tip in the hardening
agent.
[0080] In an embodiment of the seventh aspect, certain of the
present embodiments further comprise curing the membrane to harden
the hardening agent.
[0081] In an embodiment of the seventh aspect, the hardening agent
comprises cyanoacrylate.
BRIEF DESCRIPTION OF THE DRAWINGS
[0082] The various present embodiments now will be discussed in
detail with an emphasis on highlighting the advantageous features.
These embodiments depict the novel and non-obvious sensors for
continuous analyte monitoring, and related methods shown in the
accompanying drawings, which are for illustrative purposes only.
These drawings include the following figures, in which like
numerals indicate like parts:
[0083] FIG. 1 is a schematic cross-sectional view of a continuous
analyte sensor according to the present embodiments;
[0084] FIGS. 2A-2H are schematic side views of example shapes of
tissue-piercing tips for a continuous analyte sensor according to
the present embodiments;
[0085] FIGS. 3A-3D are top perspective views of additional
continuous analyte sensors according to the present
embodiments;
[0086] FIG. 4 is a continuous analyte sensor according to the
present embodiments;
[0087] FIG. 5 is a front perspective view of a system for inserting
a continuous analyte sensor into a host according to the present
embodiments;
[0088] FIG. 6 is a front perspective view of another system for
inserting a continuous analyte sensor into a host according to the
present embodiments;
[0089] FIG. 7 is a continuous analyte sensor according to the
present embodiments;
[0090] FIG. 8 is a continuous analyte sensor according to the
present embodiments;
[0091] FIG. 9 is a continuous analyte sensor according to the
present embodiments; and
[0092] FIG. 10 is a continuous analyte sensor according to the
present embodiments.
DETAILED DESCRIPTION
[0093] The following detailed description describes the present
embodiments with reference to the drawings. In the drawings,
reference numbers label elements of the present embodiments. These
reference numbers are reproduced below in connection with the
discussion of the corresponding drawing features.
[0094] The drawings and their descriptions may indicate sizes,
shapes and configurations of the various components. Such
depictions and descriptions should not be interpreted as limiting.
Alternative sizes, shapes and configurations are also contemplated
as within the scope of the present embodiments. Also, the drawings,
and their written descriptions, indicate that certain components of
the apparatus are formed integrally, and certain other components
are formed as separate pieces. Components shown and described
herein as being formed integrally may in alternative embodiments be
formed as separate pieces. Further, components shown and described
herein as being formed as separate pieces may in alternative
embodiments be formed integrally. As used herein the term integral
describes a single unitary piece.
Overview
[0095] The embodiments described herein provide various mechanisms
for directly inserting a transcutaneous sensor into a host without
the use of a separate applicator, i.e., other than the sensor
device itself. Direct press insertion of a transcutaneous sensor
(e.g., an electrode) having a wire-like geometry, especially a fine
wire, may be technically challenging because of buckling risks
associated with the sensor. Direct press insertion of a sensor also
presents challenges relating to damage during the insertion process
to the membrane disposed on the sensor. Without membrane
protection, the membrane may be stripped off from the sensor or be
mechanically damaged during the insertion process. The embodiments
described herein are designed to overcome the aforementioned
challenges by providing miniaturized sensor devices capable of
providing structural support (e.g., in the form of
mechanical/structural properties such as column strength) for
direct insertion of a transcutaneous sensor and capable of
protecting the membrane from damage during the insertion
process.
[0096] FIG. 1 illustrates a schematic side view of one embodiment
of a transcutaneous sensor device 100 configured to continuously
measure analyte concentration (e.g., glucose concentration) in a
host to provide a data stream representative of the host's analyte
concentration, in accordance with the present embodiments. Sensors
such as the one illustrated in FIG. 1 are sometimes referred to as
"tack" sensors, due to their resemblance to a thumbtack.
[0097] In the particular embodiment illustrated in FIG. 1, the
sensor device 100 comprises an in vivo portion 102 (also referred
to as a sensor unit) configured for insertion under the host's skin
104, and an ex vivo portion 106 configured to remain above the
host's skin surface after sensor insertion. The in vivo portion 102
comprises a tissue-piercing element 108 configured for piercing the
host's skin 104, and a sensor body 110. The sensor body 110
comprises a support member 112 including one or more electrodes,
and a membrane 114 disposed over at least a portion of the support
member 112. The support member 112 may also be referred to as a
sensor body 112, and the two terms are used interchangeably
herein.
[0098] The ex vivo portion 106 comprises a mounting unit 116 that
may include a sensor electronics unit (not shown) embedded or
detachably secured therein, or alternatively may be configured to
operably connect to a separate sensor electronics unit. Further
details regarding the sensor device 100 and its components may be
found in U.S. Patent Application Publication No. 2011/0077490, the
disclosure of which is incorporated herein in its entirety.
Tissue-piercing Element
[0099] The tissue-piercing element 108 of the sensor device 100 is
configured to pierce the host's skin 104, and to open and define a
passage for insertion of the sensor body 110 into a tissue of the
host. In some embodiments, the tissue-piercing element 108 may be
integral with the support member 112. In other embodiments, the
tissue-piercing element 108 may be a discrete component. In such
embodiments, the tissue-piercing element 108 may be secured to the
support member 112, such as with an adhesive. Alternatively, the
tissue-piercing element 108 may merely abut a blunt distal face of
the support member 112 and/or the membrane 114. In such
embodiments, an outer sleeve or band (not shown) may encircle a
junction of the tissue-piercing element 108 and the support member
112/membrane 114.
[0100] The skin generally comprises multiple layers, including the
epidermis, dermis, and subcutaneous layers. The epidermis comprises
a number of layers within its structure including the stratum
corneum, which is the outermost layer and is generally from about
10 to 20 microns thick, and the stratum germinativum, which is the
deepest layer of the epidermis. While the epidermis generally does
not contain blood vessels, it exchanges metabolites by diffusion to
and from the dermis. While not wishing to be bound by theory, it is
believed that because the stratum germinativum is supported by
vascularization for survival, the interstitial fluid at the stratum
germinativum sufficiently represents a host's analyte (e.g.,
glucose) levels. Beneath the epidermis is the dermis, which is from
about 1 mm to about 3 mm thick and contains blood vessels,
lymphatics, and nerves. The subcutaneous layer lies underneath the
dermis and is mostly comprised of fat. The subcutaneous layer
serves to insulate the body from temperature extremes. It also
contains connective tissue and a small amount of blood vessels.
[0101] In some embodiments, the in vivo portion 102 of the sensor
device 100 may have a length long enough to allow for at least a
portion of the sensor body 110 to reside within the stratum
germinativum. This may be desirable in some instances because the
epidermis does not contain a substantial number of blood vessels or
nerve endings. Thus, sensor insertion may be relatively painless,
and the host may not experience much bleeding or discomfort from
the insertion. In some of these embodiments, the in vivo portion
102 of the sensor device 100 may have a length of from about 0.1 mm
to about 1.5 mm, or from about 0.2 mm to about 0.5 mm. In other
embodiments, the in vivo portion 102 of the sensor device 100 may
have a length that allows for at least a portion of the sensor body
110 to reside in the dermis layer. This may be desirable in some
instances because the dermis is well vascularized, as compared to
the subcutaneous layer, and thus may provide sufficient analytes
(e.g., glucose) for measurement and reduce measurement lags
associated with changes of analyte concentrations of a host, such
as those that occur after meals. The metabolically active tissue
near the outer dermis (and also the stratum germinativum) provides
rapid equilibrium of the interstitial fluid with blood. In some of
these embodiments, the in vivo portion 102 of the sensor device may
have a length of from about 1 mm to about 7 mm, or from about 2 mm
to about 6 mm. In still other embodiments, the in vivo portion 102
of the sensor device 100 may have a length that allows for at least
a portion of the sensor body 110 to reside in the subcutaneous
layer. While not wishing to be bound by theory, it is believed that
because the subcutaneous layer serves to insulate the body from
temperature extremes, the subcutaneous layer may reduce variations
of analyte concentration readings associated with temperature
fluctuations. In some of these embodiments, the in vivo portion 102
of the sensor device may have a length of from about 3 mm to about
10 mm, or from about 5 mm to about 7 mm.
[0102] The tissue-piercing element may have any of a variety of
geometric shapes and dimensions, including ones that minimize
tissue trauma and reduce the force required for skin penetration.
For example, in some embodiments, the tissue-piercing element may
comprise a substantially conically-shaped distal tip, as
illustrated in FIG. 1, such that the cross-sectional dimensions
(e.g., diameter) of the tissue-piercing element tapers to a point
118 at the distal end of the tip, thereby providing a sharpened
leading edge configured to facilitate skin penetration. As
illustrated in FIG. 2B, in other embodiments, the distal tip of the
tissue-piercing element may be beveled with a bevel angle a, such
as, for example, an angle of from about 5.degree. to about
66.degree., or from about 10.degree. to about 55.degree., or from
about 40.degree. to about 50.degree.. In further embodiments, one
or more surfaces of the tip may be curved, such as illustrated in
FIGS. 2C-2H and 3D, so as to facilitate skin penetration when the
sensor device is pushed downwards. In some embodiments, a curved
surface may be advantageous because it provides the tissue-piercing
element with a greater cutting surface area than a straight
surface, and thus provides a smoother and more controlled insertion
of the sensor unit through the skin. Also, a tissue-piercing
element with a curved surface may cause less trauma to the pierced
tissue than one with a straight surface.
[0103] The tissue-piercing element of the sensor device is designed
to have appropriate flexibility and hardness and sufficient column
strength to allow it to remain intact and to prevent it from
substantial buckling during insertion of the in vivo portion of the
sensor device through the skin of the host. Any of a variety of
biocompatible materials having these characteristics may be used to
form the tissue-piercing element, including, but not limited to,
metals, ceramics, semiconductors, organics, polymers, composites,
and combinations or mixtures thereof. Metals that may be used
include stainless steel (e.g., 18-8 surgical steel), nitinol, gold,
silver, nickel, titanium, tantalum, palladium, gold, and
combinations or alloys thereof, for example. Polymers that may be
used include polycarbonate, polymethacrylic acid, ethylenevinyl
acetate, polytetrafluorethylene (TEFLON.RTM.), and polyesters, for
example. In some embodiments, the tissue-piercing element may serve
as a reference electrode and comprise a conductive material, such
as a silver-containing material, for example. In certain
embodiments, the tissue-piercing element has sufficient column
strength to allow the user to press the sensor unit through the
skin using the force from a thumb or finger, without substantial
buckling of the tissue-piercing element. Accordingly, the structure
of the tissue-piercing unit does not fail when it is subjected to
resistance (e.g., axial force) associated with the penetration of
tissue and skin. In some embodiments, the tissue-piercing element
may have a column strength capable of withstanding an axial load
greater than about 0.5 Newtons, or greater than about 1 Newton, or
greater than about 2 Newtons, or greater than about 5 Newtons, or
greater than about 10 Newtons, without substantial buckling. Often,
an increase in the column thickness of an object will also increase
its column strength. In some embodiments, the base 120 of the
distal tip may have an outside diameter of from about 0.05 mm to
about 1 mm, or from about 0.1 mm to about 0.5 mm, or from about
0.15 mm to about 0.3 mm, to provide the desired column strength for
the tissue-piercing element.
[0104] Some of the tissue-piercing elements described herein are
configured to protect the membrane of the sensor body. As described
elsewhere herein, the membrane may be relatively delicate, and thus
may be damaged during insertion of the sensor unit into the host.
Consequently, any damage sustained by the membrane may affect the
sensor device's performance and its ability to function properly.
For example, in some embodiments one or more portions of the
tissue-piercing element 108 may be formed with a cross-sectional
area (along a plane transverse to the longitudinal axis of the
tissue-piercing element 108) larger than that of the sensor body
110. By having a cross-sectional area larger than that of the
sensor body 110, the tissue-piercing element 108 of the sensor
device 100 is configured to pierce the host's skin 104 and to open
and define a passage for insertion of the sensor body 110 into the
tissue. Thus, the risk of a penetration-resistance force damaging
and/or stripping the membrane 140 off from the rest of the sensor
body 110 during the insertion process is reduced. In some
embodiments, the largest dimension of the cross section transverse
to a longitudinal axis of the tissue-piercing element 108 is less
than about 0.1 mm, or less than about 0.05 mm, or less than about
0.03 mm.
[0105] In some embodiments, one or more layers of one or more
polymers and/or bioactive agents may be coated onto the
tissue-piercing element. The use of bioactive agents to coat the
surface of the tissue-piercing element may provide a release of
bioactive agents in the subcutaneous tissue during and/or after
insertion of the in vivo portion of the sensor device. In further
embodiments, one or more polymer layers may be used to control the
release rate of the one or more bioactive agents. Such polymers may
include, but are not limited to, parylene, parylene C, parylene N,
parylene F, poly(hydroxymethyl-p-xylylene-co-p-xylylene) (PHPX),
poly(lactic-co-glycolic acid) (PLGA), polyethylene-co-vinyl acetate
(PEVA), Poly-L-lactic acid (PLA), poly N-butyl methacrylate (PBMA),
phosphorylcholine, poly(isobutylene-co-styrene), polyoxyethylene
(POE), polyglycolide (PGA), (poly(L-lactic acid), poly(amic acid)
(PAA, polyethylene glycol (PEG), derivatives of one or more of
these polymers, and combinations or mixtures thereof.
[0106] In some embodiments, one or more regions of the surface of
the tissue-piercing element may comprise one or more recessed
portions (e.g., cavities, indentations, openings, grooves,
channels, etc.) configured to serve as reservoirs or depots for
holding bioactive agents. The recessed portions may be formed at
any preselected location and have any preselected depth, size,
geometrical configuration, and dimensions, in accordance with the
intended application. Use of reservoirs or depots may increase the
amount of bioactive agents the tissue-piercing element is capable
of carrying and delivering. In further embodiments, the
tissue-piercing element may be hollow with a cavity and connected
via various passages with one or more openings on its surface, so
that bioactive agents may be released from the cavity via the
openings. In some embodiments, for example as shown FIGS. 3A and
3B, the tissue-piercing element 310 comprises a pocket 312 shaped
and dimensioned to support a sensor 314 with a membrane disposed
thereon.
[0107] In certain embodiments, the in vivo portion of the sensor
device is configured to remain substantially stationary within the
tissue of the host, so that migration or motion of the sensor body
with respect to the surrounding tissue is inhibited. Migration or
motion may cause inflammation at the sensor implant site due to
irritation, and may also cause noise on the sensor signal due to
motion-related artifacts. Therefore, it may be advantageous to
provide an anchoring mechanism that provides support for the in
vivo portion of the sensor device to avoid the aforementioned
problems. In some embodiments, the tissue-piercing element may
comprise a surface with one or more regions that are textured.
Texturing may roughen the surface of the tissue-piercing element
and thereby provide a surface contour with a greater surface area
than that of a non-textured (e.g., smooth) surface. Accordingly,
the amount of bioactive agents, polymers, and/or coatings that the
tissue-piercing element may carry and be released in situ is
increased, as compared to that with a non-textured surface.
Furthermore, it is believed that a textured surface may also be
advantageous in some instances, because the increased surface area
may enhance immobilization of the in vivo portion of the sensor
device within the tissue of the host. In certain embodiments, the
tissue-piercing element may comprise a surface topography with a
porous surface (e.g. porous parylene), ridged surface, etc. In
certain embodiments, the anchoring may be provided by prongs,
spines, barbs, wings, hooks, a bulbous portion (for example, at the
distal end), an S-bend along the tissue-piercing element, a
gradually changing diameter, combinations thereof, etc., which may
be used alone or in combination to stabilize the sensor within the
subcutaneous tissue. For example, in certain embodiments, the
tissue-piercing element may comprise one or more anchoring members
configured to splay outwardly (e.g., in a direction toward a plane
perpendicular to the longitudinal axis of the sensor unit) during
or after insertion of the sensor unit. Outward deployment of the
anchoring member facilitates anchoring of the sensor unit, as it
results in the tissue-piercing element pressing against the
surrounding tissue, and thus reduces (or prevents) movement and/or
rotation of the sensor unit. In some embodiments, the anchoring
members are formed of a shape memory material, such as nitinol,
which may be configured to transform from a martensitic state to an
austenitic state at a specific temperature (e.g., room temperature
or body temperature). In the martensitic state, the anchoring
members are ductile and in a contracted configuration. In the
austenitic state, the anchoring members deploy to form a larger
predetermined shape while becoming more rigid. While nitinol is
described herein as an example of a shape memory material that may
be chosen to form the anchoring member, it should be understood
that other similar materials (e.g., shape memory material) may also
be used.
[0108] The tissue-piercing element of the sensor device may be
introduced subcutaneously at any of a variety of angles with
respect to the mounting surface (the bottom surface of the mounting
unit), and thus the skin surface. For example, in some embodiments
the distal tip of the tissue-piercing element may extend
substantially perpendicular to the mounting surface, but in other
embodiments, the distal tip may extend at an angle with respect to
the mounting surface of about 15.degree., 20.degree., 30.degree.,
40.degree., 45.degree., 60.degree., 75.degree., 80.degree.,
90.degree., 105.degree., 100.degree., 120.degree., 135.degree.,
140.degree., 150.degree., 160.degree., or 165.degree., for
example.
[0109] In alternative embodiments, to provide protection of the
membrane during insertion of the sensor device, the sensor body may
be embedded or encapsulated in a needle formed of a biodegradable
material. Following insertion, the needle gradually biodegrades,
leaving behind the sensor body which may then be activated. Any of
a variety of biodegradable materials (e.g., a non-interfering
carbohydrate) may be used. In some embodiments, the biodegradable
material may include a certain concentration of an analyte to be
measured, so that an initial calibration point of the sensor device
may be provided.
[0110] As illustrated in FIG. 1, the sensor device 100 may include
a skin-contacting mounting unit 116 configured to be secured to a
host. In some embodiments, the mounting unit 116 comprises a base
122 adapted for fastening to a host's skin. The base 122 may be
formed from a variety of hard or soft materials and may comprise a
low profile for reducing protrusion of the sensor device from the
host during use. In some embodiments, the base 122 is formed at
least partially from a flexible material configured to conform to
skin contour, so as to reduce or eliminate motion-related artifacts
associated with movement by the host. In certain embodiments, the
base 122 of the mounting unit 116 includes an adhesive material or
adhesive layer 124, also referred to as an adhesive pad, preferably
disposed on the mounting unit's bottom surface, and may include a
releasable backing layer (not shown). Thus, removing the backing
layer and pressing the base 122 of the mounting unit 116 onto the
host's skin 104 adheres the mounting unit 116 to the host's skin
104. Appropriate adhesive layers may be chosen and designed to
stretch, elongate, conform to, and/or aerate the region (e.g.
host's skin). In some embodiments, the mounting unit comprises a
guiding portion (not shown) configured to guide insertion of the
sensor device 100 through the host's skin 104 and to support a
column strength of the support member 112 such that the sensor
device 100 is capable of being inserted through the host's skin 104
without substantial buckling.
[0111] While FIG. 1 illustrates one configuration for providing
membrane protection, other sensor body configurations may also be
used. For example, some of the sensor bodies described herein may
include a support member 330 configured to partially surround a
sensor, as illustrated in FIGS. 3A and 3B, or configured to
substantially surround a sensor, as illustrated in FIG. 3C. Unlike
other embodiments described elsewhere herein, in the embodiments
illustrated in FIGS. 3A-3C, the support member 330 does not
comprise a working electrode. Rather, one or more working
electrodes are arranged as components distinct from the support
member 330. In some embodiments, the support member 330 may also
serve as a reference electrode.
[0112] In the embodiment illustrated in FIG. 3A, the support member
330 comprises a longitudinal recess 332 configured to at least
partially accommodate a sensor (e.g., a working electrode with a
membrane disposed thereon). In some embodiments, the longitudinal
recess may have a length corresponding to less than about 90% of
the length of the support member 330, or less than about 75%, or
less than about 50%, or less than about 33%, or less than about
25%. In other embodiments, the longitudinal recess may extend
substantially across the entire length of the support member 330,
as illustrated in FIG. 3B. In certain embodiments, the support
member 330 may surround more than about 10% of the outer perimeter
(e.g., circumference) of the sensor, or more than about 25%, or
more than about 33%, or more than about 50%, or more than about
75%.
[0113] As illustrated in FIG. 3C, in some embodiments wherein the
sensor (e.g., the working electrode) is substantially surrounded by
the support member 330. The support member 330 may be provided with
one or more window portions 334 (openings or slots extending
through the wall thickness of the support member 330) that expose
certain portions of the electrode to biological fluid (e.g.,
interstitial fluid), and thus allow biological fluid to diffuse
toward and contact the working electrode's electroactive surface
and the membrane disposed thereon. In this embodiment, the working
electrode and the membrane disposed thereon are essentially housed
within the support member 330, and are thus protected during
packing, handling, and/or insertion of the device. The window
portions 334 may have any of a variety of shapes and dimensions.
For example, in some embodiments, the window portions may be formed
to have a circular or substantially circular shape, but in other
embodiments, the electrode may be formed with a shape resembling an
ellipse, a polygon (e.g., triangle, square, rectangle,
parallelogram, trapezoid, pentagon, hexagon, octagon), or the like.
In certain embodiments, the window portions may comprise sections
that extend around the perimeter of the longitudinal cross section
of the support member. For example, the support member may be made
by using a hypo-tube with window portions cut out in a spiral
configuration, by ablation, etching, or other techniques.
Permeability
[0114] Conventional glucose sensors measure current in the nanoAmp
range. In contrast to conventional glucose sensors, the preferred
embodiments are configured to measure the current flow in the
picoAmp range, and in some embodiments, femtoAmps. Namely, for
every unit (mg/dL) of glucose measured, at least one picoAmp of
current is measured. In some embodiments, from about 1, 2, 3, 4, or
5 picoAmps to about 25, 50, 100, 250, or 500 picoAmps of current is
measured for every unit (mg/dl) of glucose measured.
Bioactive Agents
[0115] A variety of bioactive agents are known to promote fluid
influx or efflux. Accordingly, incorporation of bioactive agents
into the membrane may increase fluid bulk, bulk fluid flow, and/or
diffusion rates (and promoting glucose and oxygen influx), thereby
decrease non-constant noise. In some embodiments, fluid bulk and/or
bulk fluid flow are increased at (e.g., adjacent to the sensor
exterior surface) the sensor by incorporation of one or more
bioactive agents. In some embodiments, the sensor is configured to
include a bioactive agent that irritates the wound and stimulates
the release of soluble mediators that are known to cause a local
fluid influx at the wound site. In some embodiments, the sensor is
configured to include a vasodilating bioactive agent, which may
cause a local influx of fluid from the vasculature.
[0116] A variety of bioactive agents may be found useful in
preferred embodiments. Example bioactive agents include but are not
limited to blood-brain barrier disruptive agents and vasodilating
agents, vasodilating agents, angiogenic factors, and the like.
Useful bioactive agents include but are not limited to mannitol,
sodium thiosulfate, VEGF/VPF, NO, NO-donors, leptin, bradykinin,
histamines, blood components, platelet rich plasma (PRP), matrix
metalloproteinases (MMP), Basic Fibroblast Growth Factor (bFGF),
(also known as Heparin Binding Growth Factor-II and Fibroblast
Growth Factor II), Acidic Fibroblast Growth Factor (aFGF), (also
known as Heparin Binding Growth Factor-I and Fibroblast Growth
Factor-I), Vascular Endothelial Growth Factor (VEGF), Platelet
Derived Endothelial Cell Growth Factor BB (PDEGF-BB),
Angiopoietin-1, Transforming Growth Factor Beta (TGF-Beta),
Transforming Growth Factor Alpha (TGF-Alpha), Hepatocyte Growth
Factor, Tumor Necrosis Factor-Alpha (TNF-Alpha), Placental Growth
Factor (PLGF), Angiogenin, Interleukin-8 (IL-8), Hypoxia Inducible
Factor-I (HIF-1), Angiotensin-Converting Enzyme (ACE) Inhibitor
Quinaprilat, Angiotropin, Thrombospondin, Peptide KGHK, Low Oxygen
Tension, Lactic Acid, Insulin, Leptin, Copper Sulphate, Estradiol,
prostaglandins, cox inhibitors, endothelial cell binding agents
(for example, decorin or vimentin), glenipin, hydrogen peroxide,
nicotine, and Growth Hormone. Still other useful bioactive agents
include enzymes, cytotoxic or necrosing agents (e.g., pactataxyl,
actinomycin, doxorubicin, daunorubicin, epirubicin, bleomycin,
plicamycin, mitomycin), cyclophosphamide, chlorambucil, uramustine,
melphalan, bryostatins, inflammatory bacterial cell wall
components, histamines, pro-inflammatory factors and the like.
[0117] Bioactive agents may be added during manufacture of the
sensor by incorporating the desired bioactive agent in the
manufacturing material for one or more sensor layers or into an
exterior biomaterial, such as a porous silicone membrane. For
example, bioactive agents may be mixed with a solution during
membrane formation, which is subsequently applied onto the sensor
during manufacture. Alternatively, the completed sensor may be
dipped into or sprayed with a solution of a bioactive agent, for
example. The amount of bioactive agent may be controlled by varying
its concentration, varying the indwell time during dipping,
applying multiple layers until a desired thickness is reached, and
the like, as disclosed elsewhere herein. In an alternative
embodiment, the bioactive agent is microencapsulated before
application to the sensor. For example, microencapsulated bioactive
agent may be sprayed onto a completed sensor or incorporated into a
structure, such as an outer mesh layer or a shedding layer.
Microencapsulation may offer increased flexibility in controlling
bioactive agent release rate, time of release occurrence and/or
release duration.
[0118] Chemical systems/methods of irritation may be incorporated
into an exterior sensor structure, such as the biointerface
membrane (described elsewhere herein) or a shedding layer that
releases the irritating agent into the local environment. For
example, in some embodiments, a "shedding layer" releases (e.g.,
sheds or leaches) molecules into the local vicinity of the sensor
and may speed up osmotic fluid shifts. In some embodiments, a
shedding layer may provide a mild irritation and encourage a mild
inflammatory/foreign body response, thereby preventing cells from
stabilizing and building up an ordered, fibrous capsule and
promoting fluid pocket formation.
[0119] A shedding layer may be constructed of any convenient,
biocompatible material, include but not limited to hydrophilic,
degradable materials such as polyvinylalcohol (PVA), PGC,
Polyethylene oxide (PEO), polyethylene glycol-polyvinylpyrrolidone
(PEG-PVP) blends, PEG-sucrose blends, hydrogels such as
polyhydroxyethyl methacrylate (pHEMA), polymethyl methacrylate
(PMMA) or other polymers with quickly degrading ester linkages. In
certain embodiment, absorbable suture materials, which degrade to
compounds with acid residues, may be used. The acid residues are
chemical irritants that stimulate inflammation and wound healing.
In certain embodiments, these compounds include glycolic acid and
lactic acid based polymers, polyglactin, polydioxone, polydyconate,
poly(dioxanone), poly(trimethylene carbonate) copolymers, and poly
(caprolactone) homopolymers and copolymers, and the like.
[0120] In other example embodiments, the shedding layer may be a
layer of materials listed elsewhere herein for the first domain,
including copolymers or blends with hydrophilic polymers such as
polyvinylpyrrolidone (PVP), polyhydroxyethyl methacrylate,
polyvinylalcohol, polyacrylic acid, polyethers, such as
polyethylene glycol, and block copolymers thereof including, for
example, di-block, tri-block, alternating, random and graft
copolymers (block copolymers are discussed in U.S. Pat. No.
4,803,243 and U.S. Patent). In one preferred embodiment, the
shedding layer is comprised of polyurethane and a hydrophilic
polymer. For example, the hydrophilic polymer may be
polyvinylpyrrolidone. In one preferred embodiment, the shedding
layer is polyurethane comprising not less than 5 weight percent
polyvinylpyrrolidone and not more than 45 weight percent
polyvinylpyrrolidone. Preferably, the shedding layer comprises not
less than 20 weight percent polyvinylpyrrolidone and not more than
35 weight percent polyvinylpyrrolidone and, most preferably,
polyurethane comprising about 27 weight percent
polyvinylpyrrolidone.
[0121] In other example embodiments, the shedding layer may include
a silicone elastomer, such as a silicone elastomer and a
poly(ethylene oxide) and poly(propylene oxide) co-polymer blend, as
disclosed in copending U.S. patent application Ser. No. 11/404,417
filed Apr. 14, 2006. In one embodiment, the silicone elastomer is a
dimethyl- and methylhydrogen-siloxane copolymer. In one embodiment,
the silicone elastomer comprises vinyl substituents. In one
embodiment, the silicone elastomer is an elastomer produced by
curing a MED-4840 mixture. In one embodiment, the copolymer
comprises hydroxy substituents. In one embodiment, the co-polymer
is a triblock poly(ethylene oxide)-poly(propylene
oxide)-poly(ethylene oxide) polymer. In one embodiment, the
co-polymer is a triblock poly(propylene oxide)-poly(ethylene
oxide)-poly(propylene oxide) polymer. In one embodiment, the
co-polymer is a PLURONIC.RTM. polymer. In one embodiment, the
co-polymer is PLURONIC.RTM. F-127. In one embodiment, at least a
portion of the co-polymer is cross-linked. In one embodiment, from
about 5% w/w to about 30% w/w of the membrane is the
co-polymer.
[0122] A shedding layer may take any shape or geometry, symmetrical
or asymmetrical, to promote fluid influx in a desired location of
the sensor, such as the sensor head or the electrochemically
reactive surfaces, for example. Shedding layers may be located on
one side of sensor or both sides. In another example, the shedding
layer may be applied to only a small portion of the sensor or the
entire sensor.
[0123] In one example embodiment, a shedding layer comprising
polyethylene oxide (PEO) is applied to the exterior of the sensor,
where the tissue surrounding the sensor may directly access the
shedding layer. PEO leaches out of the shedding layer and is
ingested by local cells that release pro-inflammatory factors. The
pro-inflammatory factors diffuse through the surrounding tissue and
stimulate an inflammation response that includes an influx of
fluid. Accordingly, early noise may be reduced or eliminated and
sensor function may be improved.
[0124] In another example embodiment, the shedding layer is applied
to the sensor in combination with an outer porous layer, such as a
mesh or a porous biointerface as disclosed elsewhere herein. In one
embodiment, local cells access the shedding layer through the
through pores of a porous silicone biointerface. In one example,
the shedding layer material is applied to the sensor prior to
application of the porous silicone. In another example, the
shedding layer material may be absorbed into the lower portion of
the porous silicone (e.g., the portion of the porous silicone that
will be proximal to the sensor after the porous silicone has been
applied to the sensor) prior to application of the porous silicone
to the sensor.
Wound Suppression
[0125] Non-constant noise may be decreased by wound suppression
(e.g., during sensor insertion), in some embodiments. Wound
suppression includes any systems or methods by which an amount of
wounding that occurs upon sensor insertion is reduced and/or
eliminated. While not wishing to be bound by theory, it is believed
that if wounding is suppressed or at least significantly reduced,
the sensor will be surrounded by substantially normal tissue (e.g.,
tissue that is substantially similar to the tissue prior to sensor
insertion). Substantially normal tissue is believed to have a lower
metabolism than wounded tissue, producing fewer interferents and
reducing early noise.
[0126] Wounds may be suppressed by adaptation of the sensor's
architecture to one that either suppresses wounding or promotes
rapid healing, such as an architecture that does not cause
substantial wounding (e.g., an architecture configured to prevent
wounding), an architecture that promotes wound healing, an
anti-inflammatory architecture, etc. In one example embodiment, the
sensor is configured to have a low profile, a zero-footprint or a
smooth surface. For example, the sensor may be formed of
substantially thin wires, such as wires from about 50 .mu.m to
about 116 .mu.m in diameter, for example. Preferably, the sensor is
small enough to fit within a very small gauge needle, such as a 30,
31, 32, 33, 34, or 35 gauge needle (or smaller) on the Stubs scale,
for example. In general, a smaller needle, the more reduces the
amount of wounding during insertion. For example, a very small
needle may reduce the amount of tissue disruption and thereby
reduce the subsequent wound healing response. In an alternative
embodiment, the sensor's surface is smoothed with a lubricious
coating, to reduce wounding upon sensor insertion.
[0127] Wounding may also be reduced by inclusion of
wound-suppressive agents (bioactive agents) that either reduce the
amount of initial wounding or suppress the wound healing process.
While not wishing to be bound by theory, it is believed that
application of a wound-suppressing agent, such as an
anti-inflammatory, an immunosuppressive agent, an anti-infective
agent, or a scavenging agent, to the sensor may create a locally
quiescent environment and suppress wound healing. In a quiescent
environment, bodily processes, such as the increased cellular
metabolism associated with wound healing, may minimally affect the
sensor. If the tissue surrounding the sensor is undisturbed, it may
continue its normal metabolism and promote sensor function.
[0128] In some embodiment, useful compounds and/or factors for
suppressing wounding include but are not limited to
first-generation H.sub.1-receptor antagonists: ethylenediamines
(e.g., mepyramine (pyrilamine), antazoline), ethanolamines (e.g.,
diphenhydramine, carbinoxamine, doxylamine, clemastine, and
dimenhydrinate), alkylamines (pheniramine, chlorphenamine
(chlorpheniramine), dexchlorphenamine, brompheniramine, and
triprolidine), piperazines (cyclizine, hydroxyzine, and meclizine),
and tricyclics (promethazine, alimemazine (trimeprazine),
cyproheptadine, and azatadine); second-generation H.sub.i-receptor
antagonists such as acrivastine, astemizole, cetirizine,
loratadine, mizolastine, azelastine, levocabastine, and
olopatadine; mast cell stabilizers such as cromoglicate (cromolyn)
and nedocromil; anti-inflammatory agents, such as acetometaphen,
aminosalicylic acid, aspirin, celecoxib, choline magnesium
trisalicylate, diclofenac potassium, diclofenac sodium, diflunisal,
etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin,
interleukin (IL)-10, IL-6 mutein, anti-IL-6 iNOS inhibitors (e.g.,
L-NMDA), Interferon, ketoprofen, ketorolac, leflunomide, melenamic
acid, mycophenolic acid, mizoribine, nabumetone, naproxen, naproxen
sodium, oxaprozin, piroxicam, rofecoxib, salsalate, sulindac, and
tolmetin; corticosteroids such as cortisone, hydrocortisone,
methylprednisolone, prednisone, prednisolone, betamethesone,
beclomethasone dipropionate, budesonide, dexamethasone sodium
phosphate, flunisolide, fluticasone propionate, paclitaxel,
tacrolimus, tranilast, triamcinolone acetonide, betamethasone,
fluocinolone, fluocinonide, betamethasone dipropionate,
betamethasone valerate, desonide, desoximetasone, fluocinolone,
triamcinolone, triamcinolone acetonide, clobetasol propionate, and
dexamethasone; immunosuppressive and/or immunomodulatory agents
such as anti-proliferative, cell-cycle inhibitors (e.g.,
paclitaxel, cytochalasin D, infiximab), taxol, actinomycin,
mitomycin, thospromote VEGF, estradiols, NO donors, QP-2,
tacrolimus, tranilast, actinomycin, everolimus, methothrexate,
mycophenolic acid, angiopeptin, vincristing, mitomycine, statins, C
MYC antisense, sirolimus (and analogs), RestenASE,
2-chloro-deoxyadenosine, PCNA Ribozyme, batimstat, prolyl
hydroxylase inhibitors, PPARy ligands (for example troglitazone,
rosiglitazone, pioglitazone), halofuginone, C-proteinase
inhibitors, probucol, BCP671, EPC antibodies, catchins, glycating
agents, endothelin inhibitors (for example, Ambrisentan,
Tesosentan, Bosentan), Statins (for example, Cerivastatin), E. coli
heat-labile enterotoxin, and advanced coatings; anti-infective
agents, such as anthelmintics (mebendazole); antibiotics such as
aminoclycosides (gentamicin, neomycin, tobramycin), antifungal
antibiotics (amphotericin b, fluconazole, griseofulvin,
itraconazole, ketoconazole, nystatin, micatin, tolnaftate),
cephalosporins (cefaclor, cefazolin, cefotaxime, ceftazidime,
ceftriaxone, cefuroxime, cephalexin), beta-lactam antibiotics
(cefotetan, meropenem), chloramphenicol, macrolides (azithromycin,
clarithromycin, erythromycin), penicillins (penicillin G sodium
salt, amoxicillin, ampicillin, dicloxacillin, nafcillin,
piperacillin, ticarcillin), tetracyclines (doxycycline,
minocycline, tetracycline), bacitracin; clindamycin; colistimethate
sodium; polymyxin b sulfate; vancomycin; antivirals including
acyclovir, amantadine, didanosine, efavirenz, foscarnet,
ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir,
saquinavir, silver, stavudine, valacyclovir, valganciclovir,
zidovudine; quinolones (ciprofloxacin, levofloxacin); sulfonamides
(sulfadiazine, sulfisoxazole); sulfones (dapsone); furazolidone;
metronidazole; pentamidine; sulfanilamidum crystallinum;
gatifloxacin; and sulfamethoxazole/trimethoprim; interferent
scavengers, such as superoxide dismutase (SOD), thioredoxin,
glutathione peroxidase and catalase, anti-oxidants, such as uric
acid and vitamin C, iron compounds, Heme compounds, and some heavy
metals; artificial protective coating components, such as albumin,
fibrin, collagen, endothelial cells, wound closure chemicals, blood
products, platelet-rich plasma, growth factors and the like.
[0129] While not wishing to be bound by theory, it is believed
that, in addition to the analyte sensor configurations described
elsewhere herein, application of a lubricious coating to the sensor
may substantially reduce and/or suppress noise occurrence by
substantially preventing injury to the host. Accordingly, in some
embodiments, a lubricious coating may be applied to the in vivo
portion of the sensor to reduce the foreign body response to the
implanted sensor. The term "lubricous coating" as used herein is
used in its ordinary sense, including without limitation, a surface
treatment that provides a reduced surface friction. A variety of
polymers are suitable for use as a lubricious sensor coating, such
as but not limited to Teflon, polyethylene, polycarbonate,
polyurethane, poly(ethylene oxide), poly(ethylene
oxide)-poly(propylene oxide) copolymers, and the like. In one
example embodiment, one or more layers of HydroMed.TM., a
polyether-polyurethane manufactured by CardioTech International,
Inc. (Wilmington, Mass.) is applied to the sensor (e.g., over the
resistance domain).
Dissolvable Tip
[0130] Sensors such as those described above are sometimes referred
to as "tack" sensors, due to their resemblance to a thumbtack. One
aspect of the present embodiments includes the realization that
tack sensors include a sharpened tip that remains implanted in the
tissue throughout the usable life of the sensor. Leaving the
sharpened tip in vivo for an extended period of time may cause
trauma to surrounding tissue, leading to scarring and inhibition of
wound healing. Some of the present embodiments provide solutions to
this problem. In some embodiments, the tip is configured to
dissolve during the implantable sensor session, for example, within
about 3, 5, 7 or 10 days.
[0131] As described above, and with reference to FIG. 1, the
tissue-piercing element 108 may be a discrete component, separate
from, for example, the sensor body 112. In such embodiments, the
sensor body 112 may include a blunt tip or distal face 126. The
tissue-piercing element 108 similarly includes a blunt proximal
face 128 that abuts the sensor body tip 126. As described above,
the tissue-piercing element 108 may or may not be secured to the
sensor body 112.
[0132] In some embodiments, the tissue-piercing element 108 may
comprise a biodegradable material, or a material that rapidly
dissolves upon insertion into the host. Upon implantation,
degradation of the tissue-piercing element 108 may be spontaneous
with acid residues. In such embodiments, any sensor membrane(s) is
desirably pH insensitive. A rate of degradation of the
tissue-piercing element 108 depends upon the amount of tip material
present. For example, the material may biodegrade/dissolve within
three days after insertion into the host, or within two days, or
one day, or twelve hours, or six hours, or three hours, or two
hours, or one hour. In certain embodiments, the material may
dissolve within a timeframe before which the sensor begins
operating. In such embodiments, the dissolved material of the
tissue-piercing element 108 may not interfere with sensor
calibration.
[0133] Example materials for the tissue-piercing element 108
include at least one of a salt, a metallic salt, a sugar, a
synthetic polymer, a glue or adhesive (such as cyanoacrylate),
polylactic acid (PLA), polyglycolic acid, poly(lactic-co-glycolic
acid) (PLGA), a polyanhydride, a polyphosphazene, or any material
with glass-like properties. In particular, PLA, PLGA, and
polyanhydrides all have sufficient hardness for this type of
application. For example, a hardness of the tissue-piercing element
108 may be in the range of 35 D to 55 D, such as for example 45
D.
[0134] In some embodiments, the material of the tissue-piercing
element 108 may be tuned or modified to achieve desired properties,
such as dissolution time, hardness, etc. For example, the
tissue-piercing element 108 may be processed with annealing and
hardening cycles, and/or cross-linking. Cross-linking may be, for
example, light based, such as irradiation with UV light. In some
embodiments, the tuning may comprise combining materials. For
example, the hardness of the tissue-piercing element 108 may be
improved by incorporating hydroxyapatite in a blend, similar to
some bone implants. Such a blend dramatically increases hardness.
Also, these inclusions tend to lead to faster dissolution
times.
[0135] If a polymer material is selected for the tissue-piercing
element 108, it may have a crystallinity, which can also be defined
by a Rockwell Hardness. For example, the material may have a
Rockwell Hardness of about 25D-65D, such as about 45D. An adequate
Rockwell Hardness enables the polymer to undergo various processing
steps without tearing or damage to the polymer.
[0136] In some embodiments, the tissue-piercing element 108 may
comprise a coating that covers at least a portion of the sensor
body 112, including the sensor tip 126. For example, with reference
to FIG. 4, a length L of the distal end of the sensor body 412 and
membrane 414 may be dipped in a liquid bath (not shown). The length
L may be chosen to coat enough of the sensor tip to achieve good
adhesion without covering any electrodes on the sensor. For
example, L may in the range of 0.1-4 mm, such as 2-3 mm. As the
sensor is withdrawn from the bath, the coating remains over the
length L, and extends distally from the sensor body tip 426,
forming a dissolvable tissue-piercing tip 408. After the coating
cures, the portion extending from the sensor tip may be sharpened
to produce a tissue-piercing coating tip 418.
[0137] In certain example embodiments, a viscosity of the liquid
bath is below 100 cP, and the withdrawal rate is 20-30 in/sec, with
an immediate exposure to UV (or heat) cross-linking to cure and
build thickness. A tip mold or draw-through fixture that clamps and
cures in one step in order to form a sharp cone shape is
advantageous.
[0138] Another embodiment to create a sharp sensor tip with a
polymer is to apply a voltage to the material while it is being
cured. The voltage causes the polymer to modify its shape to a
point. The sharp tip remains when the curing is completed and the
voltage is removed. Curing could comprise irradiating, drying,
heating, etc. Another embodiment comprises heating the material and
drawing it out like glass.
[0139] As discussed above, the sensor 400 may include one or more
aspects that either suppress wounding, or promote rapid healing, or
both. In certain embodiments, these aspects may be present in the
dissolvable tip 408. For example, one or more bioactive agents may
be integrated into the dissolvable tip 408 by combining it with the
material of the liquid bath during the dipping process.
Alternatively, before or after curing, the dissolvable tip 408 may
be dipped in a subsequent liquid bath that coats the dissolvable
tip 408 with one or more bioactive agents. Example bioactive agents
are discussed at length above and will not be repeated here.
However, certain bioactive agents may, for example, induce osmotic
pressure or oncotic pressure.
[0140] In certain embodiments, the material of the dissolvable tip
408 may have an effect on the sensor 400. For example, if the
dissolvable tip 408 is a salt, it could set up an osmotic pressure
gradient that may pull fluids to the tissue surrounding the sensor
400, causing it to startup faster or avoid early signal
attenuation.
Dissolvable Needle
[0141] Some of the present embodiments relate to sensors that
require a needle for insertion into the host. For example, with
reference to FIG. 5, the sensor 500 may be contained within a lumen
504 of a needle 502. Another aspect of the present embodiments
includes the realization that the need to remove the needle after
sensor insertion adds complexity to the insertion process,
including the need to electrically connect the sensor to sensor
electronics after insertion. Some of the present embodiments
provide solutions to this problem.
[0142] With reference to FIG. 5, the needle 502 may be similar to a
standard hypodermic needle 502, including a lumen 504 and a sharp
distal tip 506. However, the material of the needle 502 may be
biodegradable, or capable of dissolving after insertion into a
host. The material and material properties of the needle 502 may be
similar to those discussed above with respect to the dissolvable
tissue-piercing tip 506. These materials and material properties
are discussed at length above, and will not be repeated here.
However, polyanhydrides are one particularly advantageous material
for the needle 502, as they may form tubes readily and those in
turn may be sharpened by cutting.
[0143] In some embodiments, the sensor 500 may be received within
the lumen 504 but not attached to the needle 502 (FIG. 5), for
example may be held via friction force within the needle and/or
couple to a base, such as base 122 as shown in FIG. 1. In other
embodiments, the sensor 500 may be attached to the needle 502 (FIG.
6) using mechanical or chemical coupling methodologies, as may be
appreciated by one skilled in the art.
[0144] In the present embodiments, since the needle 502 is
biodegradable/dissolvable, it does not need to be removed from the
host after the sensor 500 is inserted. Instead, the needle 502
harmlessly biodegrades, thereby eliminating the traumatic tip 506
and leaving behind the sensor 500. The dissolvable needle 502 thus
simplifies the process of inserting the sensor 500 into the host.
In addition, since the needle 502 does not need to be withdrawn,
the sensor 500 may be electrically connected to sensor electronics
(not shown) prior to insertion. This aspect advantageously
eliminates the need to connect the sensor 500 to sensor electronics
after insertion, which may be challenging.
[0145] As with the embodiments of the dissolvable tissue-piercing
tip 506 discussed above, the present dissolvable needle 502 may
include one or more bioactive agents to suppress wounding and/or
promote rapid wound healing. These bioactive agents may be similar
to those discussed above, and may be applied to/integrated into the
needle 502 using the same techniques discussed above.
[0146] In certain embodiments, the needle 502 may be at least
partially dissolvable. In such embodiments, the needle may have
stronger and weaker (or more and less dissolvable) portions, such
that in vivo the weaker portions dissolve more quickly and the
stronger portions then break away from one another. The stronger
portions may ultimately dissolve, albeit more slowly than the
weaker portions. Such embodiments may be described as
"fractionate," referring to how the weaker portions dissolve
quickly allowing the hard segments, such as PLA or PGA, that
provide sufficient strength during insertion, to fragment away,
while not harming the body during or after sensor insertion.
Membrane Hardening Agent
[0147] One aspect of the present embodiments includes the
realization that the material of analyte sensor membranes is soft,
and tends to peel back as the sensor advances into tissue. This
problem is especially acute for sensors that are formed by a
process in which they are first coated with a membrane and then
sharpened at the tip. This process exposes the sensor body, and
leaves a thin coating of the membrane surrounding the sides of the
sensor body at the tip. Some of the present embodiments provide
solutions to this problem.
[0148] FIG. 7 illustrates a sensor unit 700 similar to the sensor
device 100 described above and shown in FIG. 1. The sensor unit 700
includes a sensor body 702 at least partially covered by a membrane
704. Rather than having a discrete tissue-piercing element, as in
the previous embodiments, instead the distal end 706 of the sensor
body 702 and membrane 704 are sharpened to form a tissue-piercing
tip 708. Since the sensor is sharpened after being coated with the
membrane 704, a portion of the sensor body 702 is exposed at the
sharpened tip 708. In an alternative embodiment illustrated in FIG.
8, the sensor body 802 may be sharpened prior to being coated with
the membrane 804, so that the sharpened tip 808 is covered with
membrane 804.
[0149] In both of the embodiments illustrated in FIGS. 7 and 8, the
soft membrane 704, 804 is susceptible to peeling back as the sensor
advances through tissue during the process of being inserted into
the host. Also, due to its very small diameter, the sensor of FIGS.
7 and 8 may lack the column strength necessary to be inserted
through the host's skin without substantial buckling. To solve
these problems, certain of the present embodiments provide a
hardening agent 900 that either covers the membrane 902 (FIG. 9) or
is integrated into the membrane 902 (FIG. 10). The hardening agent
900 provides increased column strength to the sensor body 904 so
that the sensor unit 906 is capable of being inserted through the
host's skin 908 without substantial buckling. The hardening agent
900 may also increase adhesion of the membrane 902 to the sensor
body 904 and/or stiffen the membrane 902 so that it is more
resistant to peeling back as the sensor advances through tissue
during the process of being inserted into the host. Preferably,
however, the hardening agent 900 allows analyte permeability within
the membrane 902 so that the ability of the sensor to function is
not compromised.
[0150] While FIGS. 9 and 10 illustrate embodiments in which a tip
910 of the sensor body 904 is exposed through the membrane
902/hardening agent 900, the present embodiments also contemplate
that the tip 910 of the sensor body 904 could be covered by the
membrane 902/hardening agent 900, similar to the embodiment of FIG.
8. Where the tip 910 of the sensor body 904 is exposed through the
membrane 902/hardening agent 900, in certain embodiments the
material of sensor body 904 is selected so that it does not react
with a selected analyte and/or product of an analyte reaction. Such
a reaction may create background current, which may adversely
affect the performance of the sensor.
[0151] In one embodiment, the material of the sensor body 904 may
be formed with a core that does not react with hydrogen peroxide.
One such sensor body is platinum cladding on tantalum, where the
tantalum core does not react with hydrogen peroxide or create
additional background signal due to its electrochemical properties.
The small amount of exposed platinum may not significantly
contribute to the background signal.
[0152] In certain embodiments, the hardening agent 900 comprises
cyanoacrylate. Cyanoacrylate is an advantageous material to use for
this application, because it may permeate into the membrane, it
cures quickly, it is very hard, and it may be machined after curing
if needed. Cyanoacrylate may also deaden any enzyme that is on the
tip, and coat any electrochemically active surfaces. Other example
materials include epoxies and UV adhesives.
[0153] In one embodiment, a method of making a sensor device
comprises coating a wire with a membrane. The coated wire is then
cut to a desired length to form a sensor wire having a tip. Example
methods for performing these steps are described in U.S. Patent
Application Publication No. 2011/0027453, the entire contents of
which are hereby incorporated by reference herein. The coated
sensor wire is then exposed to a hardening agent such that the
membrane absorbs the hardening agent. Then, if necessary, the
hardening agent is cured.
[0154] Exposing the coated sensor wire to the hardening agent may
comprise dipping at least the sensor tip in a liquid bath of the
hardening agent. After the sensor wire is withdrawn from the liquid
bath, the membrane is cured to harden the hardening agent.
Thereafter, the sensor tip may be sharpened to form a sharp point
capable of piercing tissue. In alternative embodiments, the sensor
wire may be sharpened prior to applying the membrane to the sensor
wire, or after applying the membrane to the sensor wire but prior
to applying the hardening agent.
[0155] In embodiments in which the sensor tip is sharpened after
the membrane and hardening agent are applied, a deadening agent may
be applied to the sharpened sensor tip to deaden any active
surfaces exposed during the sharpening step. For example, platinum
(Pt) or enzyme layer may be considered "active surfaces." In some
embodiments, the deadening agent may comprise cyanoacrylate or a
silane. Silanes may be particularly advantageous, since they may be
lubricious, which may help the sensor penetrate into skin.
[0156] In embodiments that include a deadening agent, the deadening
agent may be applied using vapor deposition, such as chemical vapor
deposition (CVD) or physical vapor deposition (PVD). For example, a
two-step application process may be used comprising a masking agent
and then a spray agent followed by a rinse cycle.
[0157] In another embodiment, a method of making a sensor device
comprises coating a wire with a membrane. The coated wire is then
cut to a desired length to form a sensor wire having a tip. The
coated wire is then exposed to a hardening agent such that the
hardening agent covers the membrane. Additional process steps may
then proceed similar to those in the foregoing embodiment, such as
curing, sharpening, etc.
[0158] In another embodiment, a method of making a sensor device
comprises cutting a wire to a desired length to form a sensor wire
having a tip. The sensor tip is then sharpened to form a sharp
point capable of piercing tissue. The sensor wire is then coated,
including the sharpened sensor tip, with a membrane. The coated
sensor wire is then exposed to a hardening agent such that the
membrane absorbs the hardening agent. Additional process steps may
then proceed similar to those in the foregoing embodiment, such as
curing, etc.
[0159] In another embodiment, a method of making a sensor device
comprises cutting a wire to a desired length to form a sensor wire
having a tip. The sensor tip is then sharpened to form a sharp
point capable of piercing tissue. The sensor wire is then coated,
including the sharpened sensor tip, with a membrane. By coating the
membrane, the host's fluid is separated from the enzyme by the
protective membrane system, avoiding leaching of the enzyme into
the host and ensuring a controlled pathway of diffusion of the
host's fluid through the membrane system, including the enzyme. The
coated sensor wire is then exposed to a hardening agent such that
the hardening agent covers the membrane. Additional process steps
may then proceed similar to those in the foregoing embodiment, such
as curing, etc.
[0160] In any of the foregoing embodiments, the wire may be a shape
memory metal (or a more rigid metal like Ti). In such embodiments,
the wire may be held in a first position, which may be curved or
straight, and during the insertion process the wire returns to its
memorized shape, which may be curved or straight. The return to the
memorized shape may release stored spring energy in the wire,
creating a whipping action that facilitates piercing the skin.
[0161] Methods and devices that are suitable for use in conjunction
with aspects of the preferred embodiments are disclosed in U.S.
Pat. No. 4,757,022; U.S. Pat. No. 4,994,167; U.S. Pat. No.
6,001,067; U.S. Pat. No. 6,558,321; U.S. Pat. No. 6,702,857; U.S.
Pat. No. 6,741,877; U.S. Pat. No. 6,862,465; U.S. Pat. No.
6,931,327; U.S. Pat. No. 7,074,307; U.S. Pat. No. 7,081,195; U.S.
Pat. No. 7,108,778; U.S. Pat. No. 7,110,803; U.S. Pat. No.
7,134,999; U.S. Pat. No. 7,136,689; U.S. Pat. No. 7,192,450; U.S.
Pat. No. 7,226,978; U.S. Pat. No. 7,276,029; U.S. Pat. No.
7,310,544; U.S. Pat. No. 7,364,592; U.S. Pat. No. 7,366,556; U.S.
Pat. No. 7,379,765; U.S. Pat. No. 7,424,318; U.S. Pat. No.
7,460,898; U.S. Pat. No. 7,467,003; U.S. Pat. No. 7,471,972; U.S.
Pat. No. 7,494,465; U.S. Pat. No. 7,497,827; U.S. Pat. No.
7,519,408; U.S. Pat. No. 7,583,990; U.S. Pat. No. 7,591,801; U.S.
Pat. No. 7,599,726; U.S. Pat. No. 7,613,491; U.S. Pat. No.
7,615,007; U.S. Pat. No. 7,632,228; U.S. Pat. No. 7,637,868; U.S.
Pat. No. 7,640,048; U.S. Pat. No. 7,651,596; U.S. Pat. No.
7,654,956; U.S. Pat. No. 7,657,297; U.S. Pat. No. 7,711,402; U.S.
Pat. No. 7,713,574; U.S. Pat. No. 7,715,893; U.S. Pat. No.
7,761,130; U.S. Pat. No. 7,771,352; U.S. Pat. No. 7,774,145; U.S.
Pat. No. 7,775,975; U.S. Pat. No. 7,778,680; U.S. Pat. No.
7,783,333; U.S. Pat. No. 7,792,562; U.S. Pat. No. 7,797,028; U.S.
Pat. No. 7,826,981; U.S. Pat. No. 7,828,728; U.S. Pat. No.
7,831,287; U.S. Pat. No. 7,835,777; U.S. Pat. No. 7,857,760; U.S.
Pat. No. 7,860,545; U.S. Pat. No. 7,875,293; U.S. Pat. No.
7,881,763; U.S. Pat. No. 7,885,697; U.S. Pat. No. 7,896,809; U.S.
Pat. No. 7,899,511; U.S. Pat. No. 7,901,354; U.S. Pat. No.
7,905,833; U.S. Pat. No. 7,914,450; U.S. Pat. No. 7,917,186; U.S.
Pat. No. 7,920,906; U.S. Pat. No. 7,925,321; U.S. Pat. No.
7,927,274; U.S. Pat. No. 7,933,639; U.S. Pat. No. 7,935,057; U.S.
Pat. No. 7,946,984; U.S. Pat. No. 7,949,381; U.S. Pat. No.
7,955,261; U.S. Pat. No. 7,959,569; U.S. Pat. No. 7,970,448; U.S.
Pat. No. 7,974,672; U.S. Pat. No. 7,976,492; U.S. Pat. No.
7,979,104; U.S. Pat. No. 7,986,986; U.S. Pat. No. 7,998,071; U.S.
Pat. No. 8,000,901; U.S. Pat. No. 8,005,524; U.S. Pat. No.
8,005,525; U.S. Pat. No. 8,010,174; U.S. Pat. No. 8,027,708; U.S.
Pat. No. 8,050,731; U.S. Pat. No. 8,052,601; U.S. Pat. No.
8,053,018; U.S. Pat. No. 8,060,173; U.S. Pat. No. 8,060,174; U.S.
Pat. No. 8,064,977; U.S. Pat. No. 8,073,519; U.S. Pat. No.
8,073,520; U.S. Pat. No. 8,118,877; U.S. Pat. No. 8,128,562; U.S.
Pat. No. 8,133,178; U.S. Pat. No. 8,150,488; U.S. Pat. No.
8,155,723; U.S. Pat. No. 8,160,669; U.S. Pat. No. 8,160,671; U.S.
Pat. No. 8,167,801; U.S. Pat. No. 8,170,803; U.S. Pat. No.
8,195,265; U.S. Pat. No. 8,206,297; U.S. Pat. No. 8,216,139; U.S.
Pat. No. 8,229,534; U.S. Pat. No. 8,229,535; U.S. Pat. No.
8,229,536; U.S. Pat. No. 8,231,531; U.S. Pat. No. 8,233,958; U.S.
Pat. No. 8,233,959; U.S. Pat. No. 8,249,684; U.S. Pat. No.
8,251,906; U.S. Pat. No. 8,255,030; U.S. Pat. No. 8,255,032; U.S.
Pat. No. 8,255,033; U.S. Pat. No. 8,257,259; U.S. Pat. No.
8,260,393; U.S. Pat. No. 8,265,725; U.S. Pat. No. 8,275,437; U.S.
Pat. No. 8,275,438; U.S. Pat. No. 8,277,713; U.S. Pat. No.
8,280,475; U.S. Pat. No. 8,282,549; U.S. Pat. No. 8,282,550; U.S.
Pat. No. 8,285,354; U.S. Pat. No. 8,287,453; U.S. Pat. No.
8,290,559; U.S. Pat. No. 8,290,560; U.S. Pat. No. 8,290,561; U.S.
Pat. No. 8,290,562; U.S. Pat. No. 8,292,810; U.S. Pat. No.
8,298,142; U.S. Pat. No. 8,311,749; U.S. Pat. No. 8,313,434; U.S.
Pat. No. 8,321,149; U.S. Pat. No. 8,332,008; U.S. Pat. No.
8,346,338; U.S. Pat. No. 8,364,229; U.S. Pat. No. 8,369,919; U.S.
Pat. No. 8,374,667; U.S. Pat. No. 8,386,004; and U.S. Pat. No.
8,394,021.
[0162] Methods and devices that are suitable for use in conjunction
with aspects of the preferred embodiments are disclosed in U.S.
Patent Publication No. 2003-0032874-A1; U.S. Patent Publication No.
2005-0033132-A1; U.S. Patent Publication No. 2005-0051427-A1; U.S.
Patent Publication No. 2005-0090607-A1; U.S. Patent Publication No.
2005-0176136-A1; U.S. Patent Publication No. 2005-0245799-A1; U.S.
Patent Publication No. 2006-0015020-A1; U.S. Patent Publication No.
2006-0016700-A1; U.S. Patent Publication No. 2006-0020188-A1; U.S.
Patent Publication No. 2006-0020190-A1; U.S. Patent Publication No.
2006-0020191-A1; U.S. Patent Publication No. 2006-0020192-A1; U.S.
Patent Publication No. 2006-0036140-A1; U.S. Patent Publication No.
2006-0036143-A1; U.S. Patent Publication No. 2006-0040402-A1; U.S.
Patent Publication No. 2006-0068208-A1; U.S. Patent Publication No.
2006-0142651-A1; U.S. Patent Publication No. 2006-0155180-A1; U.S.
Patent Publication No. 2006-0198864-A1; U.S. Patent Publication No.
2006-0200020-A1; U.S. Patent Publication No. 2006-0200022-A1; U.S.
Patent Publication No. 2006-0200970-A1; U.S. Patent Publication No.
2006-0204536-A1; U.S. Patent Publication No. 2006-0224108-A1; U.S.
Patent Publication No. 2006-0235285-A1; U.S. Patent Publication No.
2006-0249381-A1; U.S. Patent Publication No. 2006-0252027-A1; U.S.
Patent Publication No. 2006-0253012-A1; U.S. Patent Publication No.
2006-0257995-A1; U.S. Patent Publication No. 2006-0258761-A1; U.S.
Patent Publication No. 2006-0263763-A1; U.S. Patent Publication No.
2006-0270922-A1; U.S. Patent Publication No. 2006-0270923-A1; U.S.
Patent Publication No. 2007-0027370-A1; U.S. Patent Publication No.
2007-0032706-A1; U.S. Patent Publication No. 2007-0032718-A1; U.S.
Patent Publication No. 2007-0045902-A1; U.S. Patent Publication No.
2007-0059196-A1; U.S. Patent Publication No. 2007-0066873-A1; U.S.
Patent Publication No. 2007-0173709-A1; U.S. Patent Publication No.
2007-0173710-A1; U.S. Patent Publication No. 2007-0208245-A1; U.S.
Patent Publication No. 2007-0208246-A1; U.S. Patent Publication No.
2007-0232879-A1; U.S. Patent Publication No. 2008-0045824-A1; U.S.
Patent Publication No. 2008-0083617-A1; U.S. Patent Publication No.
2008-0086044-A1; U.S. Patent Publication No. 2008-0108942-A1; U.S.
Patent Publication No. 2008-0119703-A1; U.S. Patent Publication No.
2008-0119704-A1; U.S. Patent Publication No. 2008-0119706-A1; U.S.
Patent Publication No. 2008-0183061-A1; U.S. Patent Publication No.
2008-0183399-A1; U.S. Patent Publication No. 2008-0188731-A1; U.S.
Patent Publication No. 2008-0189051-A1; U.S. Patent Publication No.
2008-0194938-A1; U.S. Patent Publication No. 2008-0197024-A1; U.S.
Patent Publication No. 2008-0200788-A1; U.S. Patent Publication No.
2008-0200789-A1; U.S. Patent Publication No. 2008-0200791-A1; U.S.
Patent Publication No. 2008-0214915-A1; U.S. Patent Publication No.
2008-0228054-A1; U.S. Patent Publication No. 2008-0242961-A1; U.S.
Patent Publication No. 2008-0262469-A1; U.S. Patent Publication No.
2008-0275313-A1; U.S. Patent Publication No. 2008-0287765-A1; U.S.
Patent Publication No. 2008-0306368-A1; U.S. Patent Publication No.
2008-0306434-A1; U.S. Patent Publication No. 2008-0306435-A1; U.S.
Patent Publication No. 2008-0306444-A1; U.S. Patent Publication No.
2009-0018424-A1; U.S. Patent Publication No. 2009-0030294-A1; U.S.
Patent Publication No. 2009-0036758-A1; U.S. Patent Publication No.
2009-0036763-A1; U.S. Patent Publication No. 2009-0043181-A1; U.S.
Patent Publication No. 2009-0043182-A1; U.S. Patent Publication No.
2009-0043525-A1; U.S. Patent Publication No. 2009-0045055-A1; U.S.
Patent Publication No. 2009-0062633-A1; U.S. Patent Publication No.
2009-0062635-A1; U.S. Patent Publication No. 2009-0076360-A1; U.S.
Patent Publication No. 2009-0099436-A1; U.S. Patent Publication No.
2009-0124877-A1; U.S. Patent Publication No. 2009-0124879-A1; U.S.
Patent Publication No. 2009-0124964-A1; U.S. Patent Publication No.
2009-0131769-A1; U.S. Patent Publication No. 2009-0131777-A1; U.S.
Patent Publication No. 2009-0137886-A1; U.S. Patent Publication No.
2009-0137887-A1; U.S. Patent Publication No. 2009-0143659-A1; U.S.
Patent Publication No. 2009-0143660-A1; U.S. Patent Publication No.
2009-0156919-A1; U.S. Patent Publication No. 2009-0163790-A1; U.S.
Patent Publication No. 2009-0178459-A1; U.S. Patent Publication No.
2009-0192366-A1; U.S. Patent Publication No. 2009-0192380-A1; U.S.
Patent Publication No. 2009-0192722-A1; U.S. Patent Publication No.
2009-0192724-A1; U.S. Patent Publication No. 2009-0192751-A1; U.S.
Patent Publication No. 2009-0203981-A1; U.S. Patent Publication No.
2009-0216103-A1; U.S. Patent Publication No. 2009-0240120-A1; U.S.
Patent Publication No. 2009-0240193-A1; U.S. Patent Publication No.
2009-0242399-A1; U.S. Patent Publication No. 2009-0242425-A1; U.S.
Patent Publication No. 2009-0247855-A1; U.S. Patent Publication No.
2009-0247856-A1; U.S. Patent Publication No. 2009-0287074-A1; U.S.
Patent Publication No. 2009-0299155-A1; U.S. Patent Publication No.
2009-0299156-A1; U.S. Patent Publication No. 2009-0299162-A1; U.S.
Patent Publication No. 2010-0010331-A1; U.S. Patent Publication No.
2010-0010332-A1; U.S. Patent Publication No. 2010-0016687-A1; U.S.
Patent Publication No. 2010-0016698-A1; U.S. Patent Publication No.
2010-0030484-A1; U.S. Patent Publication No. 2010-0036215-A1; U.S.
Patent Publication No. 2010-0036225-A1; U.S. Patent Publication No.
2010-0041971-A1; U.S. Patent Publication No. 2010-0045465-A1; U.S.
Patent Publication No. 2010-0049024-A1; U.S. Patent Publication No.
2010-0076283-A1; U.S. Patent Publication No. 2010-0081908-A1; U.S.
Patent Publication No. 2010-0081910-A1; U.S. Patent Publication No.
2010-0087724-A1; U.S. Patent Publication No. 2010-0096259-A1; U.S.
Patent Publication No. 2010-0121169-A1; U.S. Patent Publication No.
2010-0161269-A1; U.S. Patent Publication No. 2010-0168540-A1; U.S.
Patent Publication No. 2010-0168541-A1; U.S. Patent Publication No.
2010-0168542-A1; U.S. Patent Publication No. 2010-0168543-A1; U.S.
Patent Publication No. 2010-0168544-A1; U.S. Patent Publication No.
2010-0168545-A1; U.S. Patent Publication No. 2010-0168546-A1; U.S.
Patent Publication No. 2010-0168657-A1; U.S. Patent Publication No.
2010-0174157-A1; U.S. Patent Publication No. 2010-0174158-A1; U.S.
Patent Publication No. 2010-0174163-A1; U.S. Patent Publication No.
2010-0174164-A1; U.S. Patent Publication No. 2010-0174165-A1; U.S.
Patent Publication No. 2010-0174166-A1; U.S. Patent Publication No.
2010-0174167-A1; U.S. Patent Publication No. 2010-0179401-A1; U.S.
Patent Publication No. 2010-0179402-A1; U.S. Patent Publication No.
2010-0179404-A1; U.S. Patent Publication No. 2010-0179408-A1; U.S.
Patent Publication No. 2010-0179409-A1; U.S. Patent Publication No.
2010-0185065-A1; U.S. Patent Publication No. 2010-0185069-A1; U.S.
Patent Publication No. 2010-0185070-A1; U.S. Patent Publication No.
2010-0185071-A1; U.S. Patent Publication No. 2010-0185075-A1; U.S.
Patent Publication No. 2010-0191082-A1; U.S. Patent Publication No.
2010-0198035-A1; U.S. Patent Publication No. 2010-0198036-A1; U.S.
Patent Publication No. 2010-0212583-A1; U.S. Patent Publication No.
2010-0217557-A1; U.S. Patent Publication No. 2010-0223013-A1; U.S.
Patent Publication No. 2010-0223022-A1; U.S. Patent Publication No.
2010-0223023-A1; U.S. Patent Publication No. 2010-0228109-A1; U.S.
Patent Publication No. 2010-0228497-A1; U.S. Patent Publication No.
2010-0240975-A1; U.S. Patent Publication No. 2010-0240976 C1; U.S.
Patent Publication No. 2010-0261987-A1; U.S. Patent Publication No.
2010-0274107-A1; U.S. Patent Publication No. 2010-0280341-A1; U.S.
Patent Publication No. 2010-0286496-A1; U.S. Patent Publication No.
2010-0298684-A1; U.S. Patent Publication No. 2010-0324403-A1; U.S.
Patent Publication No. 2010-0331656-A1; U.S. Patent Publication No.
2010-0331657-A1; U.S. Patent Publication No. 2011-0004085-A1; U.S.
Patent Publication No. 2011-0009727-A1; U.S. Patent Publication No.
2011-0024043-A1; U.S. Patent Publication No. 2011-0024307-A1; U.S.
Patent Publication No. 2011-0027127-A1; U.S. Patent Publication No.
2011-0027453-A1; U.S. Patent Publication No. 2011-0027458-A1; U.S.
Patent Publication No. 2011-0028815-A1; U.S. Patent Publication No.
2011-0028816-A1; U.S. Patent Publication No. 2011-0046467-A1; U.S.
Patent Publication No. 2011-0077490-A1; U.S. Patent Publication No.
2011-0118579-A1; U.S. Patent Publication No. 2011-0124992-A1; U.S.
Patent Publication No. 2011-0125410-A1; U.S. Patent Publication No.
2011-0130970-A1; U.S. Patent Publication No. 2011-0130971-A1; U.S.
Patent Publication No. 2011-0130998-A1; U.S. Patent Publication No.
2011-0144465-A1; U.S. Patent Publication No. 2011-0178378-A1; U.S.
Patent Publication No. 2011-0190614-A1; U.S. Patent Publication No.
2011-0201910-A1; U.S. Patent Publication No. 2011-0201911-A1; U.S.
Patent Publication No. 2011-0218414-A1; U.S. Patent Publication No.
2011-0231140-A1; U.S. Patent Publication No. 2011-0231141-A1; U.S.
Patent Publication No. 2011-0231142-A1; U.S. Patent Publication No.
2011-0253533-A1; U.S. Patent Publication No. 2011-0263958-A1; U.S.
Patent Publication No. 2011-0270062-A1; U.S. Patent Publication No.
2011-0270158-A1; U.S. Patent Publication No. 2011-0275919-A1; U.S.
Patent Publication No. 2011-0290645-A1; U.S. Patent Publication No.
2011-0313543-A1; U.S. Patent Publication No. 2011-0320130-A1; U.S.
Patent Publication No. 2012-0035445-A1; U.S. Patent Publication No.
2012-0040101-A1; U.S. Patent Publication No. 2012-0046534-A1; U.S.
Patent Publication No. 2012-0078071-A1; U.S. Patent Publication No.
2012-0108934-A1; U.S. Patent Publication No. 2012-0130214-A1; U.S.
Patent Publication No. 2012-0172691-A1; U.S. Patent Publication No.
2012-0179014-A1; U.S. Patent Publication No. 2012-0186581-A1; U.S.
Patent Publication No. 2012-0190953-A1; U.S. Patent Publication No.
2012-0191063-A1; U.S. Patent Publication No. 2012-0203467-A1; U.S.
Patent Publication No. 2012-0209098-A1; U.S. Patent Publication No.
2012-0215086-A1; U.S. Patent Publication No. 2012-0215087-A1; U.S.
Patent Publication No. 2012-0215201-A1; U.S. Patent Publication No.
2012-0215461-A1; U.S. Patent Publication No. 2012-0215462-A1; U.S.
Patent Publication No. 2012-0215496-A1; U.S. Patent Publication No.
2012-0220979-A1; U.S. Patent Publication No. 2012-0226121-A1; U.S.
Patent Publication No. 2012-0228134-A1; U.S. Patent Publication No.
2012-0238852-A1; U.S. Patent Publication No. 2012-0245448-A1; U.S.
Patent Publication No. 2012-0245855-A1; U.S. Patent Publication No.
2012-0255875-A1; U.S. Patent Publication No. 2012-0258748-A1; U.S.
Patent Publication No. 2012-0259191-A1; U.S. Patent Publication No.
2012-0260323-A1; U.S. Patent Publication No. 2012-0262298-A1; U.S.
Patent Publication No. 2012-0265035-A1; U.S. Patent Publication No.
2012-0265036-A1; U.S. Patent Publication No. 2012-0265037-A1; U.S.
Patent Publication No. 2012-0277562-A1; U.S. Patent Publication No.
2012-0277566-A1; U.S. Patent Publication No. 2012-0283541-A1; U.S.
Patent Publication No. 2012-0283543-A1; U.S. Patent Publication No.
2012-0296311-A1; U.S. Patent Publication No. 2012-0302854-A1; U.S.
Patent Publication No. 2012-0302855-A1; U.S. Patent Publication No.
2012-0323100-A1; U.S. Patent Publication No. 2013-0012798-A1; U.S.
Patent Publication No. 2013-0030273-A1; U.S. Patent Publication No.
2013-0035575-A1; U.S. Patent Publication No. 2013-0035865-A1; U.S.
Patent Publication No. 2013-0035871-A1; U.S. Patent Publication No.
2005-0056552-A1; and U.S. Patent Publication No.
2005-0182451-A1.
[0163] Methods and devices that are suitable for use in conjunction
with aspects of the preferred embodiments are disclosed in U.S.
application Ser. No. 09/447,227 filed on Nov. 22, 1999 and entitled
"DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS"; U.S.
application Ser. No. 12/828,967 filed on Jul. 1, 2010 and entitled
"HOUSING FOR AN INTRAVASCULAR SENSOR"; U.S. application Ser. No.
13/461,625 filed on May 1, 2012 and entitled "DUAL ELECTRODE SYSTEM
FOR A CONTINUOUS ANALYTE SENSOR"; U.S. application Ser. No.
13/594,602 filed on Aug. 24, 2012 and entitled "POLYMER MEMBRANES
FOR CONTINUOUS ANALYTE SENSORS"; U.S. application Ser. No.
13/594,734 filed on Aug. 24, 2012 and entitled "POLYMER MEMBRANES
FOR CONTINUOUS ANALYTE SENSORS"; U.S. application Ser. No.
13/607,162 filed on Sep. 7, 2012 and entitled "SYSTEM AND METHODS
FOR PROCESSING ANALYTE SENSOR DATA FOR SENSOR CALIBRATION"; U.S.
application No. 13/624,727 filed on Sep. 21, 2012 and entitled
"SYSTEMS AND METHODS FOR PROCESSING AND TRANSMITTING SENSOR DATA";
U.S. application Ser. No. 13/624,808 filed on Sep. 21, 2012 and
entitled "SYSTEMS AND METHODS FOR PROCESSING AND TRANSMITTING
SENSOR DATA"; U.S. application Ser. No. 13/624,812 filed on Sep.
21, 2012 and entitled "SYSTEMS AND METHODS FOR PROCESSING AND
TRANSMITTING SENSOR DATA"; U.S. application Ser. No. 13/732,848
filed on Jan. 2, 2013 and entitled "ANALYTE SENSORS HAVING A
SIGNAL-TO-NOISE RATIO SUBSTANTIALLY UNAFFECTED BY NON-CONSTANT
NOISE"; U.S. application Ser. No. 13/733,742 filed on Jan. 3, 2013
and entitled "END OF LIFE DETECTION FOR ANALYTE SENSORS"; U.S.
application Ser. No. 13/733,810 filed on Jan. 3, 2013 and entitled
"OUTLIER DETECTION FOR ANALYTE SENSORS"; U.S. application Ser. No.
13/742,178 filed on Jan. 15, 2013 and entitled "SYSTEMS AND METHODS
FOR PROCESSING SENSOR DATA"; U.S. application Ser. No. 13/742,694
filed on Jan. 16, 2013 and entitled "SYSTEMS AND METHODS FOR
PROVIDING SENSITIVE AND SPECIFIC ALARMS"; U.S. application Ser. No.
13/742,841 filed on Jan. 16, 2013 and entitled "SYSTEMS AND METHODS
FOR DYNAMICALLY AND INTELLIGENTLY MONITORING A HOST'S GLYCEMIC
CONDITION AFTER AN ALERT IS TRIGGERED"; and U.S. application Ser.
No. 13/747,746 filed on Jan. 23, 2013 and entitled "DEVICES,
SYSTEMS, AND METHODS TO COMPENSATE FOR EFFECTS OF TEMPERATURE ON
IMPLANTABLE SENSORS".
[0164] The above description presents the best mode contemplated
for carrying out the present invention, and of the manner and
process of making and using it, in such full, clear, concise, and
exact terms as to enable any person skilled in the art to which it
pertains to make and use this invention. This invention is,
however, susceptible to modifications and alternate constructions
from that discussed above that are fully equivalent. Consequently,
this invention is not limited to the particular embodiments
disclosed. On the contrary, this invention covers all modifications
and alternate constructions coming within the spirit and scope of
the invention as generally expressed by the following claims, which
particularly point out and distinctly claim the subject matter of
the invention. While the disclosure has been illustrated and
described in detail in the drawings and foregoing description, such
illustration and description are to be considered illustrative or
exemplary and not restrictive.
[0165] All references cited herein are incorporated herein by
reference in their entirety. To the extent publications and patents
or patent applications incorporated by reference contradict the
disclosure contained in the specification, the specification is
intended to supersede and/or take precedence over any such
contradictory material.
[0166] Unless otherwise defined, all terms (including technical and
scientific terms) are to be given their ordinary and customary
meaning to a person of ordinary skill in the art, and are not to be
limited to a special or customized meaning unless expressly so
defined herein. It should be noted that the use of particular
terminology when describing certain features or aspects of the
disclosure should not be taken to imply that the terminology is
being re-defined herein to be restricted to include any specific
characteristics of the features or aspects of the disclosure with
which that terminology is associated. Terms and phrases used in
this application, and variations thereof, especially in the
appended claims, unless otherwise expressly stated, should be
construed as open ended as opposed to limiting. As examples of the
foregoing, the term `including` should be read to mean `including,
without limitation,` including but not limited to,' or the like;
the term `comprising` as used herein is synonymous with
`including,` `containing,` or `characterized by,` and is inclusive
or open-ended and does not exclude additional, unrecited elements
or method steps; the term `having` should be interpreted as `having
at least;` the term `includes` should be interpreted as `includes
but is not limited to;` the term `example` is used to provide
exemplary instances of the item in discussion, not an exhaustive or
limiting list thereof; adjectives such as `known`, `normal`,
`standard`, and terms of similar meaning should not be construed as
limiting the item described to a given time period or to an item
available as of a given time, but instead should be read to
encompass known, normal, or standard technologies that may be
available or known now or at any time in the future; and use of
terms like `preferably,` preferred,"desired,' or `desirable,` and
words of similar meaning should not be understood as implying that
certain features are critical, essential, or even important to the
structure or function of the invention, but instead as merely
intended to highlight alternative or additional features that may
or may not be utilized in a particular embodiment of the invention.
Likewise, a group of items linked with the conjunction `and` should
not be read as requiring that each and every one of those items be
present in the grouping, but rather should be read as `and/or`
unless expressly stated otherwise. Similarly, a group of items
linked with the conjunction `or` should not be read as requiring
mutual exclusivity among that group, but rather should be read as
`and/or` unless expressly stated otherwise.
[0167] Where a range of values is provided, it is understood that
the upper and lower limit, and each intervening value between the
upper and lower limit of the range is encompassed within the
embodiments.
[0168] With respect to the use of substantially any plural and/or
singular terms herein, those having skill in the art can translate
from the plural to the singular and/or from the singular to the
plural as is appropriate to the context and/or application. The
various singular/plural permutations may be expressly set forth
herein for sake of clarity. The indefinite article `a` or `an` does
not exclude a plurality. A single processor or other unit may
fulfill the functions of several items recited in the claims. The
mere fact that certain measures are recited in mutually different
dependent claims does not indicate that a combination of these
measures cannot be used to advantage. Any reference signs in the
claims should not be construed as limiting the scope.
[0169] It will be further understood by those within the art that
if a specific number of an introduced claim recitation is intended,
such an intent will be explicitly recited in the claim, and in the
absence of such recitation no such intent is present. For example,
as an aid to understanding, the following appended claims may
contain usage of the introductory phrases `at least one` and `one
or more` to introduce claim recitations. However, the use of such
phrases should not be construed to imply that the introduction of a
claim recitation by the indefinite articles `a` or `an` limits any
particular claim containing such introduced claim recitation to
embodiments containing only one such recitation, even when the same
claim includes the introductory phrases `one or more` or `at least
one` and indefinite articles such as `a` or `an` (e.g., `a` and/or
`an` should typically be interpreted to mean `at least one` or `one
or more`); the same holds true for the use of definite articles
used to introduce claim recitations. In addition, even if a
specific number of an introduced claim recitation is explicitly
recited, those skilled in the art will recognize that such
recitation should typically be interpreted to mean at least the
recited number (e.g., the bare recitation of `two recitations,`
without other modifiers, typically means at least two recitations,
or two or more recitations). Furthermore, in those instances where
a convention analogous to `at least one of A, B, and C, etc.` is
used, in general such a construction is intended in the sense one
having skill in the art would understand the convention (e.g., `a
system having at least one of A, B, and C` would include but not be
limited to systems that have A alone, B alone, C alone, A and B
together, A and C together, B and C together, and/or A, B, and C
together, etc.). In those instances where a convention analogous to
`at least one of A, B, or C, etc.` is used, in general such a
construction is intended in the sense one having skill in the art
would understand the convention (e.g., `a system having at least
one of A, B, or C` would include but not be limited to systems that
have A alone, B alone, C alone, A and B together, A and C together,
B and C together, and/or A, B, and C together, etc.). It will be
further understood by those within the art that virtually any
disjunctive word and/or phrase presenting two or more alternative
terms, whether in the description, claims, or drawings, should be
understood to contemplate the possibilities of including one of the
terms, either of the terms, or both terms. For example, the phrase
`A or B` will be understood to include the possibilities of `A` or
`B` or `A and B.`
[0170] All numbers expressing quantities of ingredients, reaction
conditions, and so forth used in the specification are to be
understood as being modified in all instances by the term `about.`
Accordingly, unless indicated to the contrary, the numerical
parameters set forth herein are approximations that may vary
depending upon the desired properties sought to be obtained. At the
very least, and not as an attempt to limit the application of the
doctrine of equivalents to the scope of any claims in any
application claiming priority to the present application, each
numerical parameter should be construed in light of the number of
significant digits and ordinary rounding approaches.
[0171] Furthermore, although the foregoing has been described in
some detail by way of illustrations and examples for purposes of
clarity and understanding, it is apparent to those skilled in the
art that certain changes and modifications may be practiced.
Therefore, the description and examples should not be construed as
limiting the scope of the invention to the specific embodiments and
examples described herein, but rather to also cover all
modification and alternatives coming with the true scope and spirit
of the invention.
* * * * *